tag:blogger.com,1999:blog-73466672004884252182024-03-13T03:50:09.978-07:00SoftSimu blogsThe blogspace of SoftSimu.
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The views expressed in this blog are entirely those of the authors as listed per posting and do not represent those of our respective universities or other employers.
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License: Creative Commons</p></p>SoftSimuhttp://www.blogger.com/profile/00081179440222824736noreply@blogger.comBlogger9125tag:blogger.com,1999:blog-7346667200488425218.post-70357157931210569872014-04-08T10:18:00.000-07:002014-04-08T10:45:29.977-07:00Conformational biases of linear motifs and their roles in target binding<span style="font-size: large;"><span style="font-family: "Helvetica Neue",Arial,Helvetica,sans-serif;">Cino EA, Choy WY, Karttunen M (2013) Conformational Biases of Linear Motifs. J Phys Chem B 117:15943-15957. <a href="http://pubs.acs.org/doi/abs/10.1021/jp407536p" target="_blank">link to manuscript</a><br /><br /> Videos of our simulations of disordered proteins on <a href="http://www.flickr.com/photos/softsimu/sets/72157628579738351/">Flickr</a> and <a href="http://www.youtube.com/user/softsimu?feature=watch">YouTube</a></span></span><br />
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<span style="font-size: large;"><span style="font-family: "Helvetica Neue",Arial,Helvetica,sans-serif;"> Fig 1. p53 TAD region conformational ensemble contains a population of structures that resemble its MDM2 bound state [1].<br /><br /> Intrinsically disordered proteins (IDPs) comprise ~30% of the proteins in our bodies and have key roles in protein-protein interaction networks. Studies have shown that the structural properties of IDPs are crucial to the protein-protein interactions they participate in [1-7]. Despite their name, IDPs do not adopt completely random conformations – many IDPs have conformational propensities. These segments are called Linear Motifs (LMs), and typically consist of continuous 5-25 amino acid stretches. Interestingly, LMs are often crucial protein-protein interaction sites (Fig 1). Several recent studies have identified a number of LMs that prefer to form specific structures that resemble their complexed state while participating in protein-protein interactions (Fig 1). Based on this knowledge, efforts [4, 8] have been made to develop therapeutic LMs (peptides) with enhanced propensities to form particular structures – the idea being to either disrupt the natural protein-protein interaction, or to enhance downstream events that result due to the interaction. In either case, the goal is to elicit a therapeutic effect.</span></span><br />
<span style="font-size: large;"><span style="font-family: "Helvetica Neue",Arial,Helvetica,sans-serif;"><br /> In our <a href="http://pubs.acs.org/doi/full/10.1021/jp407536p">recent paper</a>, which is discussed in this post, the conformational propensities of Linear Motifs from several proteins (Exoenzyme S, Amphiphysin 1, β-Arrestin 2, p21, p66 and Fen1, the LxxLL motif containing protein, RIP140 and a synthetic peptide, Tcf4, and p53) were investigated using microsecond timescale equilibrium Molecular Dynamics (MD) simulations in explicit solvent. The free state conformational landscapes of the LMs were analyzed using several metrics and compared to their known conformations in complex with interacting proteins (ie. Exoenzyme S:14-3-3, Tcf4:β-Catenin and p53:MDM2).</span></span><br />
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<iframe allowfullscreen="" frameborder="0" height="383" src="//www.youtube.com/embed/7BNmKOPnKvY?list=UUsaAM5ALWtyxhDHa3_q8zxA" width="680"></iframe>
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<span style="font-size: large;"><span style="font-family: "Helvetica Neue",Arial,Helvetica,sans-serif;"> In this post, the Exoenzyme S LM, which interacts with 14-3-3, is briefly discussed. The Exoenzyme S protein contains an11 amino acid region that forms a short amphipathic helix, with the hydrophobic face pointing toward the 14-3-3 binding groove (Video 1). Microsecond timescale MD simulations of the Exoenzyme S LM (in the absence of 14-3-3) show that it had propensity for adopting structures similar to the one found in complex with 14-3-3 (Video 1). The LM was found to transition between high and low rmsds to the 14-3-3 bound state on the nanosecond timescale. In 8% of the frames the main chain rmsd was <0.15 nm, suggesting that although the uncomplexed state equilibrium favors the unfolded conformation, a population of bound state-like structures exists. To assess which features of the LM govern formation of bound-state like structures, correlations between several measurements (solvent accessible surfaces, secondary structures, compactness, and principal components) and rmsds were analyzed. One variable that was generally well correlated with bound state rmsds was the backbone dihedral angle principal components (dPCA PC1 vs. mainchain rmsd for Exoenzyme S r2=0.64) (Video 1). For further details of the Exoenzyme S and other LMs, take a look at the <a href="http://pubs.acs.org/doi/full/10.1021/jp407536p">manuscript</a>.</span></span><br />
<span style="font-size: large;"><span style="font-family: "Helvetica Neue",Arial,Helvetica,sans-serif;"><br /> The results from this work show that LMs can have distinct conformational propensities, which often resemble the structure formed after binding to a target protein. As a result, the free state structure and dynamics of LMs may hold important clues regarding binding mechanisms, affinities and specificities. The findings should be helpful in advancing our understanding of the mechanisms whereby disordered amino acid sequences bind targets, modeling disordered proteins/regions, and computational prediction of binding affinities.</span></span> <span style="font-size: large;"><span style="font-family: "Helvetica Neue",Arial,Helvetica,sans-serif;"> </span></span><br />
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<b><span style="font-size: large;"><span style="font-family: "Helvetica Neue",Arial,Helvetica,sans-serif;">References</span></span></b><br />
<span style="font-size: large;"><span style="font-family: "Helvetica Neue",Arial,Helvetica,sans-serif;"><br /></span></span> <span style="font-size: large;"><span style="font-family: "Helvetica Neue",Arial,Helvetica,sans-serif;">1. Cino EA, Choy WY, Karttunen M (2013) Conformational Biases of Linear Motifs. J Phys Chem B 117:15943-15957 <a href="http://pubs.acs.org/doi/abs/10.1021/jp407536p">link to manuscript</a> </span></span><br />
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<span style="font-size: large;"><span style="font-family: "Helvetica Neue",Arial,Helvetica,sans-serif;">2. Das, R. K.; Mao, A. H.; Pappu, R. V (2012) Unmasking Functional Motifs Within Disordered Regions of Proteins. Sci Signal 5: pe17<br /><br />3. Fuxreiter, M.; Tompa, P.; Simon, I. (2007) Local Structural Disorder Imparts Plasticity on Linear Motifs. Bioinformatics 23: 950-956<br /><br />4. Cino, E.A., Killoran, R.C., Karttunen, M., and Choy, W.Y. (2013) Binding of intrinsically disordered proteins to a protein hub. Sci Reps 3: 2305 <a href="http://www.nature.com/srep/2013/130729/srep02305/full/srep02305.html?WT.ec_id=SREP-20130730">link to manuscript</a></span></span> <span style="font-size: large;"><span style="font-family: "Helvetica Neue",Arial,Helvetica,sans-serif;"> </span></span><br />
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<span style="font-size: large;"><span style="font-family: "Helvetica Neue",Arial,Helvetica,sans-serif;">5. Khan, H., Cino, E.A., Brickenden A., Fan, J., Yang, D. and Choy, W.Y. (2013) Fuzzy Complex Formation between the Intrinsically Disordered Prothymosin α and the Kelch Domain of Keap1 Involved in the Oxidative Stress Response. J Mol Biol 425(6): 1011-1027 <a href="http://www.sciencedirect.com/science/article/pii/S0022283613000089">link to manuscript</a></span></span> <span style="font-size: large;"><span style="font-family: "Helvetica Neue",Arial,Helvetica,sans-serif;"> </span></span><br />
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<span style="font-size: large;"><span style="font-family: "Helvetica Neue",Arial,Helvetica,sans-serif;">6. Cino EA, Wong-Ekkabut J, Karttunen M, Choy WY (2011) Microsecond molecular dynamics simulations of intrinsically disordered proteins involved in the oxidative stress response. PLoS One 6: e27371 <a href="http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0027371">link to manuscript</a></span></span> <span style="font-size: large;"><span style="font-family: "Helvetica Neue",Arial,Helvetica,sans-serif;"> </span></span><br />
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<span style="font-size: large;"><span style="font-family: "Helvetica Neue",Arial,Helvetica,sans-serif;">7. Cino EA, Karttunen M, Choy WY (2012) Effects of molecular crowding on the dynamics of intrinsically disordered proteins. PLoS One 7: e49876 <a href="http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0049876">link to manuscript</a></span></span> <span style="font-size: large;"><span style="font-family: "Helvetica Neue",Arial,Helvetica,sans-serif;"> </span></span><br />
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<span style="font-size: large;"><span style="font-family: "Helvetica Neue",Arial,Helvetica,sans-serif;">8. Bernal, et al (2007) Reactivation of the p53 Tumor Suppressor Pathway by a Stapled p53 Peptide. J Am Chem Soc 129(9): 2456-2457</span></span> <span style="font-size: large;"><span style="font-family: "Helvetica Neue",Arial,Helvetica,sans-serif;"><br /></span></span>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">Cino
EA, Karttunen M, Choy WY (2012) Effects of molecular crowding on the dynamics
of intrinsically disordered proteins. <i>PLoS One </i>7:e49876. <a href="http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0049876"><span class="InternetLink"><span style="mso-bidi-font-family: "Trebuchet MS";">link to
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;"><span class="Apple-style-span" style="font-size: large;">Videos of our
simulations of disordered proteins on <a href="http://www.flickr.com/photos/softsimu/sets/72157628579738351/"><span class="InternetLink">Flickr</span></a> and <span class="InternetLink"><a href="http://www.youtube.com/user/softsimu?feature=watch">YouTube</a></span></span></span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;"><br /></span><span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;"> Inside cells the concentration of macromolecules
can reach up to 400 g/L, creating a crowded environment (Fig 1). The space
occupied by cellular molecules (proteins, nucleic acids, etc) reduces the
amount of water available, causing molecules to behave differently than they
would in more dilute environments. Most studies of proteins and other
macromolecules are conducted </span><span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;"><i style="mso-bidi-font-style: normal;">in vitro</i></span><span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">
with purified and relatively dilute samples. To accurately characterize
macromolecules and the biochemical processes they are involved in, it is
important to examine them </span><span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;"><i style="mso-bidi-font-style: normal;">in vivo</i></span><span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">, or
under conditions that mimic the crowded cellular environment.</span><br />
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<a href="http://2.bp.blogspot.com/-5sy3mA9d30w/UUHrpqXeJvI/AAAAAAAAAEk/KA4QZJGnxrY/s1600/Crowded_cytosol.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="548" src="http://2.bp.blogspot.com/-5sy3mA9d30w/UUHrpqXeJvI/AAAAAAAAAEk/KA4QZJGnxrY/s640/Crowded_cytosol.png" width="640" /></a></div>
<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;">Fig 1. Diagram illustrating the crowded cellular environment. Microtubules, actin and other proteins (blue, red and green), ribosomes (yellow and purple), RNA (pink).</span><br />
<div style="font-family: Times; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px;">
<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;"><span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;"><br /></span></span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;"><span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;"> In the crowded cellular environment, proteins are expected to behave differently than in vitro. The stability and the folding rate of a well-folded protein can be altered by the excluded volume effect produced by a high density of macromolecules. However, crowding effects on intrinsically disordered proteins (IDPs) are less explored. These proteins can be extremely dynamic and potentially sample a wide ensemble of conformations (Fig 2). The dynamic properties of IDPs are intimately related to the timescale of conformational exchange within the ensemble, which govern </span></span></div>
<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">target recognition and how these proteins function.</span></div>
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<a href="http://2.bp.blogspot.com/-Lj_vWW9m66c/UUIAgh_LBCI/AAAAAAAAAFk/iRM0zAZVkXY/s1600/rotacf.tif" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="222" src="http://2.bp.blogspot.com/-Lj_vWW9m66c/UUIAgh_LBCI/AAAAAAAAAFk/iRM0zAZVkXY/s640/rotacf.tif" width="640" /></a></div>
<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;">Fig 2. Differential dynamics between disordered and well-folded proteins. Autocorrelation functions of backbone N-H bond vectors for individual amino acids residues illustrates that the highly disordered prothymosin alpha is considerably more dynamic compared to ubiquitin. The quickly decorrelating residues in ubiquitin correspond to the terminal ends, which are considerably more flexible than the core region. The data was extracted from MD simulations of each protein in the absence of crowding agents.</span><br />
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;"> In <a href="http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0049876">this</a></span><span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;"> manuscript, we focused on determining
how molecular crowding affects the dynamics of IDPs using NMR spin-relaxation experiments.
Measurements were taken for three disordered proteins, and the well-folded
protein, ubiquitin, for comparison, in the absence and presence of crowding
agents. Our data illustrates that IDPs remain at least partially disordered
despite the presence of high concentration of other macromolecules (Fig 3).</span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;">Fig 3. <sup>1</sup>H-<sup>15</sup>N Heteronuclear Single Quantum
Coherence (HSQC) spectra in the absence (black) and presence (red) of 160 g/L
crowding agent Ficoll 70. The IDPs Prothymosin alpha, Thyroid cancer-1 and
alpha synuclein as well as the well-folded protein, ubiquitin, were examined.
Similar black and red spectra indicate that the protein structures are similar
in dilute and crowded environments.</span><br />
<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;"><br /></span>
<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;"><br /></span>
<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;"> </span><span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">Despite
this, specific regions of Thyroid-cancer-1 and Prothymosin alpha, which
encompass protein-protein interaction sites exhibited differential dynamics in
the absence and presence of high concentration of crowding agents (Fig 4). This
suggests that the crowded environment may have differential effects on the
conformational propensity of distinct regions of an IDP, which may lead to selective
stabilization of certain target-binding motifs.</span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;">Fig 4. Backbone N-H bond transverse relaxation rates for prothymosin
alpha and thyroid cancer-1 in the absence (black) and presence (red and green)
of crowding agents. Distinct regions of the proteins show differential changes
in dynamics in response to crowding.</span><br />
<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;"><br /></span>
<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;"> </span><span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">Using
an MD simulation of prothymosin alpha in the absence of crowding agents, we
have proposed a model to correlate the
observed changes in relaxation rates to the alteration in protein motions under
crowding conditions (see the <a href="http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0049876">manuscript</a>
for details). Overall, the
results show that the segmental motions of IDPs on the nanosecond timescale are
retained under crowded conditions and that IDPs function as dynamic structural
ensembles in cellular environments.</span></div>
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<b style="mso-bidi-font-weight: normal;"><span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">Our related work references<o:p></o:p></span></b></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">1.
Cino EA, Karttunen M, Choy WY (2012) Effects of molecular crowding on the
dynamics of intrinsically disordered proteins. <i>PLoS One </i>7:e49876. <span class="InternetLink"><span style="mso-bidi-font-family: "Trebuchet MS";"><a href="http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0049876">link to
manuscript</a></span></span></span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">2.
Cino
EA, Choy WY, Karttunen M (2012) Comparison of Secondary Structure Formation
Using 10 Different Force Fields in Microsecond Molecular Dynamics Simulations. <i>J
Chem Theory Comput </i>8:2725-2740. <a href="http://pubs.acs.org/doi/abs/10.1021/ct300323g?prevSearch=cino&searchHistoryKey="><span class="InternetLink"><span style="mso-bidi-font-family: "Trebuchet MS";">link to
manuscript</span></span></a><o:p></o:p></span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">3. Cino EA, Wong-Ekkabut J, Karttunen M, Choy
WY (2011) Microsecond molecular dynamics simulations of intrinsically
disordered proteins involved in the oxidative stress response. <i>PLoS One </i>6:e27371.
<span class="InternetLink"><span style="mso-bidi-font-family: "Trebuchet MS";"><a href="http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0027371">link to
manuscript</a></span></span></span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">4.
Cino E, Fan J, Yang D, Choy WY (2012) (1)H, (15)N and (13)C backbone resonance
assignments of the Kelch domain of mouse Keap1. <i>Biomol NMR Assign</i><span style="mso-bidi-font-style: italic;">. In press. </span><span class="InternetLink"><span style="mso-bidi-font-family: "Trebuchet MS"; mso-bidi-font-style: italic;"><a href="http://link.springer.com/article/10.1007/s12104-012-9398-6">link to manuscript</a></span></span></span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">5. Khan H, Cino, EA, Brickenden A, Fan J, Yang D, Choy WY (2013)
Fuzzy Complex Formation between the Intrinsically Disordered Prothymosin α and the Kelch Domain of
Keap1 Involved in the Oxidative Stress Response. <i>J Mol Biol</i> 6:1011-1027. <a href="http://www.sciencedirect.com/science/article/pii/S0022283613000089">link to manuscript</a></span></div>
<!--EndFragment-->Anonymoushttp://www.blogger.com/profile/10793105137316516499noreply@blogger.com0tag:blogger.com,1999:blog-7346667200488425218.post-5392600632560865922013-01-27T11:12:00.001-08:002013-01-27T14:46:03.127-08:00Comparing force fields for biomolecular simulations <!--[if gte mso 9]><xml>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">Cino EA, Choy WY, Karttunen M (2012)
Comparison of Secondary Structure Formation Using 10 Different Force Fields in
Microsecond Molecular Dynamics Simulations. <i>J Chem Theory Comput </i>8:2725-2740. <a href="http://pubs.acs.org/doi/abs/10.1021/ct300323g?prevSearch=cino&searchHistoryKey="><span class="InternetLink">link to manuscript</span></a><o:p></o:p></span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">
Videos of our simulations of disordered proteins on <span class="InternetLink"><a href="http://www.youtube.com/user/softsimu?feature=watch">YouTube</a> and</span> <span class="InternetLink"><a href="http://www.flickr.com/photos/softsimu/sets/72157628579738351/">Flickr</a></span></span><br />
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<img border="0" height="370" src="http://1.bp.blogspot.com/-5ihygLZlkiI/UQV5CWZuc5I/AAAAAAAAADk/zqy0Bk8eHbg/s640/fig1.png" width="640" /></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;"><b>Fig 1.</b> Structures of the NRF2 hairpin from folding simulations and
representative free energy landscape of the hairpin folding. The free
energy landscape was constructed from a 3 dimensional histogram consisting of radius
of gyration, backbone rmsd to bound state structure (PDB id: 2FLU) and distance
between 2 hydrophobic residues on opposite strands of the hairpin that make
close contacts (as determined by solution NMR for the peptide in the free
state).</span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;"><span class="Apple-style-span" style="font-size: large;"> A primary choice
in performing MD simulations is which force field to use. Currently, specific
force fields are employed depending on the system being investigated. For
example, a certain force field may give good agreement with experimental data
for a specific type of protein, but not necessarily for another. Even though
modifications to biomolecular force fields have lead to improved transferability,
further progress relies on continued testing. Ideally, these efforts will lead
to the development of fully transferable force fields.<o:p></o:p></span></span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;"><br /></span></div>
<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;">
</span><br />
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;"><span class="Apple-style-span" style="font-size: large;"><span style="mso-tab-count: 1;"></span> A good method to test force field performance
is by simulating protein folding and comparing the results to experimentally
determined protein structures. However, most proteins fold on timescales unattainable
by modern computer simulations. As a result, it can be challenging to find good
test systems. One approach has been to extract amino acid sequences encoding self-folding
motifs out of <a href="http://softsimu.blogspot.ca/2013/01/preformed-structural-elements-in-long.html">well-folded proteins</a>. While this may be a viable approach to
decrease system sizes and obtain folding events, care must be taken to ensure that
the motif does indeed fold properly in the absence of the rest of the protein. Another
approach has been to design small, fast folding proteins. However, protein
design is not an easy task. <o:p></o:p></span></span></div>
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<span class="Apple-style-span" style="font-size: large;"><span style="mso-tab-count: 1;"></span> Perhaps a better, in terms of being doable,
approach for force field testing of protein folding is to use amino acid
sequences encoding preformed structural elements (PSEs). As discussed in my <a href="http://softsimu.blogspot.ca/2013/01/preformed-structural-elements-in-long.html">January 11th post</a>, <i style="mso-bidi-font-style: normal;">intrinsically
disordered proteins </i>(IDPs) often contain PSEs to facilitate their
interactions with other proteins. The benefits of using PSEs for folding
simulations is that they are typically locally occurring features that do not
rely as heavily upon long-range contacts as structural elements in well-folded
proteins. Moreover, they often contain features that are found in well-folded
proteins, such as hydrophobic clusters and electrostatic interactions. In many
ways, PSEs can be though of as mini or micro proteins. These may be ideal
candidates for testing of force fields.</span></div>
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<a href="http://4.bp.blogspot.com/-BXbh2SiK_bo/UQV5jdKNwgI/AAAAAAAAADs/eMP_Qwkve_U/s1600/hairpin.tif" imageanchor="1"><img border="0" src="http://4.bp.blogspot.com/-BXbh2SiK_bo/UQV5jdKNwgI/AAAAAAAAADs/eMP_Qwkve_U/s1600/hairpin.tif" /></a></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;"><span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;"><b>Fig 2.</b> Example of a hairpin motif. Hairpins are composed of two antiparallel beta strands connected by a turn. They are common structural elements found in many proteins.<o:p></o:p></span></span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;"><span style="font-size: 12pt;"><span class="InternetLink"><br /></span></span></span></div>
<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;"><span style="font-size: 12pt;"><span class="InternetLink">
</span></span><span class="Apple-style-span" style="font-size: large;"> For this post, the folding of a PSE from
the protein <a href="http://softsimu.blogspot.ca/2013/01/preformed-structural-elements-in-long.html">NRF2</a> with 10 commonly used biomolecular force fields is compared.
This PSE has been studied experimentally and is known to form what is known as
a ‘hairpin’ structure (Fig. 2). Starting from an extended conformation, the
amino acid sequence encoding this hairpin has been shown to fold into a
structure consistent with experimental data in < 1 µs. However, when
comparing the folding of this structural element with commonly used force
fields, differences were observed (Fig. 1). Although many of the force fields
reproduced experimentally determined free state contacts and yielded hairpin
structures, some did not (Fig. 1). As mentioned in my <a href="http://softsimu.blogspot.ca/2013/01/preformed-structural-elements-in-long.html">January 11th post</a>, the hairpin appears to be stabilized by
hydrogen bonds and hydrophobic contacts.</span><span class="InternetLink"></span></span><br />
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;"><span class="InternetLink">
</span><span class="Apple-style-span" style="font-size: large;"> The results from this investigation
emphasize the importance of force field selection. Additionally, the work
illustrates that PSEs may be ideal candidates for force field testing. The
results obtained from folding simulations of such elements should be useful for
improving biomolecular force fields.</span></span><span class="InternetLink"></span><br />
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<b><span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">Our related work references<o:p></o:p></span></b></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">1.
Cino
EA, Choy WY, Karttunen M (2012) Comparison of Secondary Structure Formation
Using 10 Different Force Fields in Microsecond Molecular Dynamics Simulations. <i>J
Chem Theory Comput </i>8:2725-2740. <a href="http://pubs.acs.org/doi/abs/10.1021/ct300323g?prevSearch=cino&searchHistoryKey="><span class="InternetLink">link to manuscript</span></a><o:p></o:p></span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">2.
Cino
EA, Wong-Ekkabut J, Karttunen M, Choy WY (2011) Microsecond molecular dynamics
simulations of intrinsically disordered proteins involved in the oxidative
stress response. <i>PLoS One </i>6:e27371. <a href="http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0027371"><span class="InternetLink">link to manuscript</span></a></span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">3.
Cino EA, Karttunen M, Choy WY (2012) Effects of molecular crowding on the
dynamics of intrinsically disordered proteins. <i>PLoS One </i>7:e49876. <a href="http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0049876"><span class="InternetLink">link to manuscript</span></a></span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">4.
Cino E, Fan J, Yang D, Choy WY (2012) (1)H, (15)N and (13)C backbone resonance
assignments of the Kelch domain of mouse Keap1. <i>Biomol NMR Assign</i><span style="mso-bidi-font-style: italic;">. In press. </span><a href="http://link.springer.com/article/10.1007/s12104-012-9398-6"><span class="InternetLink">link to manuscript</span></a></span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">5. Khan H, Cino, EA, Brickenden A, Fan J, Yang D, Choy WY (2013)
Fuzzy Complex Formation between the Intrinsically Disordered Prothymosin α and the Kelch Domain of
Keap1 Involved in the Oxidative Stress Response. <i>J Mol Biol</i>. In press. <a href="http://www.sciencedirect.com/science/article/pii/S0022283613000089">link to manuscript</a></span><span style="font-family: 'Times New Roman'; font-size: 12pt;"><o:p></o:p></span></div>
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<!--EndFragment-->Anonymoushttp://www.blogger.com/profile/10793105137316516499noreply@blogger.com2tag:blogger.com,1999:blog-7346667200488425218.post-86106591185503755122013-01-23T05:31:00.000-08:002013-01-23T05:31:01.186-08:00Pilkington on thermodynamics and phase transitions<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="http://4.bp.blogspot.com/-C2QYCgQdTAQ/UP_lgxhQX1I/AAAAAAAAALE/Bx49BfuO2PI/s1600/pilkington-thermo.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="http://4.bp.blogspot.com/-C2QYCgQdTAQ/UP_lgxhQX1I/AAAAAAAAALE/Bx49BfuO2PI/s1600/pilkington-thermo.jpg" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Confessions of Karl Pilkington, Science Man: The Early Years </td></tr>
</tbody></table>
<br />SoftSimuhttp://www.blogger.com/profile/00081179440222824736noreply@blogger.com0tag:blogger.com,1999:blog-7346667200488425218.post-15271345922505062462013-01-22T04:29:00.000-08:002013-01-22T04:29:22.389-08:00Pilkington on the Big Bang<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="http://4.bp.blogspot.com/-mJ63BGbqFRY/UP3Xkfg-rZI/AAAAAAAAAK0/W7aQbSHsUGA/s1600/pilkington-big-bang.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="http://4.bp.blogspot.com/-mJ63BGbqFRY/UP3Xkfg-rZI/AAAAAAAAAK0/W7aQbSHsUGA/s1600/pilkington-big-bang.jpg" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Confessions of Karl Pilkington, Science Man: The Early Years </td></tr>
</tbody></table>
<br />SoftSimuhttp://www.blogger.com/profile/00081179440222824736noreply@blogger.com0tag:blogger.com,1999:blog-7346667200488425218.post-2696364776885346532013-01-21T06:30:00.002-08:002013-01-21T06:30:26.688-08:00Pilkington on snow<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="http://2.bp.blogspot.com/-Y3edvWtJkG4/UP1QgZUHauI/AAAAAAAAAKk/DR9ByKzNVzM/s1600/pilkington-snow.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="http://2.bp.blogspot.com/-Y3edvWtJkG4/UP1QgZUHauI/AAAAAAAAAKk/DR9ByKzNVzM/s1600/pilkington-snow.jpg" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Confessions of Karl Pilkington, Science Man: The Early Years </td></tr>
</tbody></table>
<br />SoftSimuhttp://www.blogger.com/profile/00081179440222824736noreply@blogger.com0tag:blogger.com,1999:blog-7346667200488425218.post-61662328801063214842013-01-21T04:55:00.000-08:002013-01-21T05:30:43.682-08:00Pilkington on superconductivity<h4>
</h4>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="http://4.bp.blogspot.com/-OnW5aEP_4Z8/UP00Ycd88jI/AAAAAAAAAKM/Gfn3wD31vV8/s1600/pilkington-1aa.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img alt="" border="0" src="http://4.bp.blogspot.com/-OnW5aEP_4Z8/UP00Ycd88jI/AAAAAAAAAKM/Gfn3wD31vV8/s1600/pilkington-1aa.jpg" title="Confessions of Karl Pilkington, Science Man: The Early Years " /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Confessions of Karl Pilkington, Science Man: The Early Years </td></tr>
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<br />SoftSimuhttp://www.blogger.com/profile/00081179440222824736noreply@blogger.com0tag:blogger.com,1999:blog-7346667200488425218.post-20646573324260231122013-01-11T14:03:00.001-08:002013-01-13T09:06:05.412-08:00Preformed structural elements in intrinsically disordered proteins<!--[if !mso]>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">Cino
EA, Wong-Ekkabut J, Karttunen M, Choy WY (2011) Microsecond molecular dynamics
simulations of intrinsically disordered proteins involved in the oxidative stress
response. <i>PLoS One </i>6:e27371. <a href="http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0027371"><span class="InternetLink">link to manuscript</span></a></span></div>
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<span style="font-size: large;"><span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;">Videos of our
simulations of disordered proteins on </span><span class="InternetLink" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;"><a href="http://www.youtube.com/user/softsimu?feature=watch" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;">YouTube</a> and</span><span style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;"> </span><a href="http://www.flickr.com/photos/softsimu/sets/72157628579738351/" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;"><span class="InternetLink">Flickr</span></a></span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;"> <span style="font-size: large;"> It was once thought that a protein must adopt a
defined three-dimensional structure to function properly. The discovery of
biologically active<i> intrinsically disordered proteins </i>(IDPs) illustrates
that some proteins are able to carry out their functions through different
mechanisms than well-folded proteins. IDPs comprise ~30% of the eukaryotic
proteome. The abundance of IDPs in organisms suggests that they are essential
for numerous functions. They are often found
to be involved in crucial signaling and regulatory functions in cells.
Therefore, it is not a surprise that IDPs are frequently associated with human
diseases, in particular cancer and neurodegenerative diseases.</span></span></div>
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<span style="font-size: large;"><a href="http://2.bp.blogspot.com/-Kf99VwQC_Zw/UPCJdniTa3I/AAAAAAAAAC4/INyEuJ_w-cQ/s1600/fig1.tif" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;"><img border="0" height="366" src="http://2.bp.blogspot.com/-Kf99VwQC_Zw/UPCJdniTa3I/AAAAAAAAAC4/INyEuJ_w-cQ/s640/fig1.tif" width="640" /></span></a></span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: small;"><b>Fig 1.</b> Structures of an IDP and a well-folded protein. The NMR
ensemble structures of the IDP (Thylakoid soluble phosphoprotein TSP9, PDB id:
2FFT) do not overlay well because its intrinsic dynamic properties allow
exchange between different conformations over time. On the other hand, the NMR
ensemble structures of the well-folded protein (Ubiquitin, PDB id: 1D3Z) illustrate
that a similar structure is maintained over time.</span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;"> <span style="font-family: "Helvetica Neue",Arial,Helvetica,sans-serif;">Despite their name, I</span>DPs do not adopt
completely random structures. Many IDPs have considerable conformational
propensities. Segments of IDPs that contain residual structure may act as <i>recognition
features for interacting with other proteins</i>. There are two methods by
which these interaction hot spots function. For some IDPs, the recognition
features contain preformed structural elements (PSEs) that resemble the bound
state, while others may couple conformational changes with target binding. For
IDPs that bind using PSEs, the bound state structure is already formed in the
unbound state. In the coupled folding and binding model, the IDP undergoes<i> a
disorder-to-order transition</i> upon binding to a target. It is important to
realize that these two interaction methods represent opposite ends of the
binding mode continuum. In most cases, binding of IDPs is probably modulated by
a combination of these two mechanisms.</span></div>
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<span style="font-size: large;"><a href="http://2.bp.blogspot.com/-99vbpiqttK8/UPCJqnAoshI/AAAAAAAAADA/x9Rdv7_ib6k/s1600/pse_diagram.tif" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;"><img border="0" height="562" src="http://2.bp.blogspot.com/-99vbpiqttK8/UPCJqnAoshI/AAAAAAAAADA/x9Rdv7_ib6k/s640/pse_diagram.tif" width="640" /></span></a></span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: small;"><b>Fig 2</b>. Binding mechanisms of IDPs. An IDP can interact with binding
partners by either folding into a bound state like conformation prior to
binding (top), encountering the binding partner and then folding (bottom), or a
combination of these two mechanisms (middle).</span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;"> </span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;"> Because
preformed elements in unbound structural ensembles of IDPs often comprise <i>protein-protein interaction sites</i>, their
identification and characterization is an area of active investigations. The
main approach is to identify preformed elements from sequence alone. Interaction hot spots in IDPs often have distinct sequence
characteristics compared to their surroundings, with the primary difference
being an <i>increased hydrophobic content</i>, which may promote local
structure formations. The main problem with relying solely upon amino acid
sequence properties to identify PSEs is the high number of false positives. In
addition bioinformatics approaches, Nuclear Magnetic Resonance (NMR)
spectroscopy has also proven to be a useful technique for detecting PSEs. The
focus of this post, however, is on using Molecular Dynamics (MD) simulations to
detect and characterize PSEs in IDP structures.</span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;"> Here,
we used MD simulations to probe the free state structures and dynamics of two
IDPs, PTMA and NRF2. These two proteins interact with a common partner, Keap1,
in order to control the cellular response to oxidative stress. Misregulation of
the oxidative stress response pathway can lead to neurodegenerative diseases,
diabetes and cancer. Compounds that can disrupt the NRF2-Keap1 interaction have
been proposed as potential therapeutic agents for enhancing the oxidative
stress response. Development of drug candidates requires an understanding of
the molecular basis of the interactions.</span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;"> By
conducting microsecond timescale MD simulations, important PSEs were identified
in the Keap1 binding regions of PTMA and NRF2. In the absence of Keap1, the
PSEs had clear resemblance to their bound state structures. NRF2, which
interacts with Keap1 with a higher affinity than PTMA formed PSEs with lower
RMSDs to its bound state structure, compared to PTMA. It appears that the
extents of bound state like structures that are formed in the absence of
binding partner have important implications in dictating the binding
thermodynamics of these proteins.</span></div>
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<span style="font-size: large;"><a href="http://1.bp.blogspot.com/-bCovdElubrQ/UPCKFELEa5I/AAAAAAAAADI/7mz1e12p74s/s1600/fig2.tif" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;"><img border="0" height="226" src="http://1.bp.blogspot.com/-bCovdElubrQ/UPCKFELEa5I/AAAAAAAAADI/7mz1e12p74s/s640/fig2.tif" width="640" /></span></a></span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: small;"><b>Fig 3.</b> Formation of PSEs with different extents of bound state
resemblance. Left: RMSDs to the bound state structures during the MD
trajectories. Right: snapshots from the MD simulations (grey) overlaid with
their bound state structures (pink).</span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;"> The MD simulations were
analyzed to determine possible reasons to explain why NRF2 forms a more bound
state like PSE compared to PTMA. The analysis suggested that NRF2 was able to
form a more compact PSE compared to PTMA. This may be attributed to NRF2
forming more hydrogen bonds. Additionally, NRF2 contains more hydrophobic amino
acids surrounding its PSE compared to PTMA, which may also promote structure
formation.</span></div>
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<span style="font-size: large;"><a href="http://2.bp.blogspot.com/-b-oYNTqq0j0/UPCKMoC_ANI/AAAAAAAAADQ/Wbr6zX6OySg/s1600/contributions_to_pses.tif" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;"><img border="0" height="430" src="http://2.bp.blogspot.com/-b-oYNTqq0j0/UPCKMoC_ANI/AAAAAAAAADQ/Wbr6zX6OySg/s640/contributions_to_pses.tif" width="640" /></span></a></span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: small;"><b>Fig 4.</b> Contributing factors to explain the different extents of
preformed structure in PTMA and NRF2. Top: percentage of structures from the MD
simulations with an end-to-end distance less than 0.7 nm. Bottom: percentage of
MD structures with 1 or more hydrogen bond.</span></div>
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<b><span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">Our related references</span></b></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">1.
Cino E, Choy WY, Karttunen M (2012) Comparison of secondary structure formation
using 10 different force fields in microsecond molecular dynamics simulations <i>J
Chem Theory Comput </i>8:2725-2740. <a href="http://pubs.acs.org/doi/abs/10.1021/ct300323g?prevSearch=cino&searchHistoryKey"><span class="InternetLink">link to manuscript</span></a></span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">2.
Cino EA, Karttunen M, Choy WY (2012) Effects of molecular crowding on the
dynamics of intrinsically disordered proteins. <i>PLoS One </i>7:e49876. <a href="http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0049876"><span class="InternetLink">link to manuscript</span></a></span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">3.
Cino E, Fan J, Yang D, Choy WY (2012) (1)H, (15)N and (13)C backbone resonance
assignments of the Kelch domain of mouse Keap1. <i>Biomol NMR Assign</i>. In press. <span class="InternetLink"><a href="http://link.springer.com/article/10.1007/s12104-012-9398-6">link to manuscript</a></span></span><br />
<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;"><br /></span>
<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">4. Khan H, Cino, EA, Brickenden A, Fan J, Yang D, Choy WY (2013) Fuzzy Complex Formation between the Intrinsically Disordered Prothymosin α and the Kelch Domain of Keap1 Involved in the Oxidative Stress Response. <i>J Mol Biol</i>. In press. <a href="http://www.sciencedirect.com/science/article/pii/S0022283613000089">link to manuscript</a></span></div>
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<b><span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">General references</span></b></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">1.
Dunker AK, et al. (2001) Intrinsically disordered protein. <i>J Mol Graph Model </i>19:26-59. <a href="http://www.sciencedirect.com/science/article/pii/S1093326300001388">link to manuscript</a></span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">2. Uversky
VN (2002) Natively unfolded proteins: a point where biology waits for physics. <i>Protein
Sci </i>11:739-56. <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2373528/">link to manuscript</a></span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">3.
Uversky VN, Oldfield CJ, Dunker AK (2008) Intrinsically disordered proteins in
human diseases: introducing the D2 concept. <i>Annu Rev Biophys </i>37:215-46. <a href="http://www.annualreviews.org/doi/abs/10.1146/annurev.biophys.37.032807.125924">link to manuscript</a></span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">4.
Wright PE, Dyson HJ (1999) Intrinsically unstructured proteins: re-assessing
the protein structure-function paradigm. <i>J Mol Biol </i>293:321-31. <a href="http://www.sciencedirect.com/science/article/pii/S0022283699931108">link to manuscript</a></span></div>
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<span class="Apple-style-span" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">5.
Lambrughi M et al. (2012) Intramolecular interactions stabilizing compact
conformations of the intrinsically disordered kinase-inhibitor domain of Sic1:
a molecular dynamics investigation. <i>Front Physiol </i>3:435. <a href="http://www.frontiersin.org/Systems_Biology/10.3389/fphys.2012.00435/abstract">link to manuscript</a></span></div>
<!--EndFragment-->Anonymoushttp://www.blogger.com/profile/10793105137316516499noreply@blogger.com3tag:blogger.com,1999:blog-7346667200488425218.post-37619173886227660752013-01-05T13:24:00.004-08:002013-01-05T13:24:57.714-08:00New blog Although I and SoftSimu have a long history wrt web presence, this blog is a new attempt. The intention is just to follow a relatively random walk through science and research related issues. The opinions here reflect only those of the respective authors and not our employers or other bodies any of us may be a member/part of. Let's see how this works out.Mikko Karttunenhttp://www.blogger.com/profile/03065382264699676522noreply@blogger.com0