Comparing force fields for biomolecular simulations

Cino EA, Choy WY, Karttunen M (2012) Comparison of Secondary Structure Formation Using 10 Different Force Fields in Microsecond Molecular Dynamics Simulations. J Chem Theory Comput 8:2725-2740. link to manuscript

Videos of our simulations of disordered proteins on YouTube and Flickr

Fig 1. 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).

       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.

       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 well-folded proteins. 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.

       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 January 11th post, intrinsically disordered proteins (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.

Fig 2. 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.

       For this post, the folding of a PSE from the protein NRF2 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 January 11th post, the hairpin appears to be stabilized by hydrogen bonds and hydrophobic contacts.

       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.

Our related work references

1. Cino EA, Choy WY, Karttunen M (2012) Comparison of Secondary Structure Formation Using 10 Different Force Fields in Microsecond Molecular Dynamics Simulations. J Chem Theory Comput 8:2725-2740. link to manuscript

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. PLoS One 6:e27371. link to manuscript

3. Cino EA, Karttunen M, Choy WY (2012) Effects of molecular crowding on the dynamics of intrinsically disordered proteins. PLoS One 7:e49876. link to manuscript

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. Biomol NMR Assign. In press. link to manuscript

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. J Mol Biol. In press. link to manuscript