Identifying native‐like protein structures using physics‐based potentials

Abstract

As the field of structural genomics matures, new methods will be required that can accurately and rapidly distinguish reliable structure predictions from those that are more dubious. We present a method based on the CHARMM gas phase implicit hydrogen force field in conjunction with a generalized Born implicit solvation term that allows one to make such discrimination. We begin by analyzing pairs of threaded structures from the EMBL database, and find that it is possible to identify the misfolded structures with over 90% accuracy. Further, we find that misfolded states are generally favored by the solvation term due to the mispairing of favorable intramolecular ionic contacts. We also examine 29 sets of 29 misfolded globin sequences from Levitt's "Decoys 'R' Us" database generated using a sequence homology-based method. Again, we find that discrimination is possible with approximately 90% accuracy. Also, even in these less distorted structures, mispairing of ionic contacts results in a more favorable solvation energy for misfolded states. This is also found to be the case for collapsed, partially folded conformations of CspA and protein G taken from folding free energy calculations. We also find that the inclusion of the generalized Born solvation term, in postprocess energy evaluation, improves the correlation between structural similarity and energy in the globin database. This significantly improves the reliability of the hypothesis that more energetically favorable structures are also more similar to the native conformation. Additionally, we examine seven extensive collections of misfolded structures created by Park and Levitt using a four-state reduced model also contained in the "Decoys 'R' Us" database. Results from these large databases confirm those obtained in the EMBL and misfolded globin databases concerning predictive accuracy, the energetic advantage of misfolded proteins regarding the solvation component, and the improved correlation between energy and structural similarity due to implicit solvation. Z-scores computed for these databases are improved by including the generalized Born implicit solvation term, and are found to be comparable to trained and knowledge-based scoring functions. Finally, we briefly explore the dynamic behavior of a misfolded protein relative to properly folded conformations. We demonstrate that the misfolded conformation diverges quickly from its initial structure while the properly folded states remain stable. Proteins in this study are shown to be more stable than their misfolded counterparts and readily identified based on energetic as well as dynamic criteria. In summary, we demonstrate the utility of physics-based force fields in identifying native-like conformations in a variety of preconstructed structural databases. The details of this discrimination are shown to be dependent on the construction of the structural database.

Performance comparison of generalized born and Poisson methods in the calculation of electrostatic solvation energies for protein structures

“…GB models have been used successfully for calculating accurate solvation energies of small molecules, 51,59,62 scoring of protein conformations, [63][64][65] evaluation of protein-ligand binding, 66 pK a predictions, 54 and implicit solvent molecular dynamics simulations. 55,66 -69 However, problems in achieving stable trajectories of native conformations when using GB for simulations have also been pointed out.…”

Implicit solvation based on generalized Born theory in different dielectric environments

“…Electronic mail: brooks@scripps.edu ͑PB͒ energies 14 -18 with average relative errors of less than 1% for the GBMV method 14 -16 when calculating solvation energies of proteins in water. The application of implicit solvent descriptions has been increasingly successful in simulation studies, 19,20 scoring of protein conformations, 21 estimates of pK a values, 22 and evaluation of protein-ligand binding free energies. 23 However, since many biological processes occur in low-dielectric environments such as cell membranes, there is a strong incentive to extend continuum approaches based on GB to such environments as well.…”

Peptide and Protein Folding and Conformational Equilibria: Theoretical Treatment of Electrostatics and Hydrogen Bonding with Implicit Solvent Models

“…The nature of these problems reinforces the point that the scoring function must be fast and accurate enough for good scoring performance, which provides motivation, challenge, and validation to the physics-based energy functions (e.g., modern molecular mechanics plus continuum dielectric solvent models). While there exists some evidence that a GB model might not help for this purpose (Morozov et al, 2003), a number of other studies have shown that the physics-based energy functions perform well in distinguishing native and near-native folds (Dominy and Brooks, 2001;Feig and Brooks, 2002;Felts et al, 2002;Zhu et al, 2003) and loop conformations (Fiser et al, 2002;Forrest and Woolf, 2003) from a large set of nonnative decoys. Recent examination of GB and PB implicit solvation models in the context of computational protein design revealed a systematic bias that the burial of polar amino acids in the protein interior is more favored than that of nonpolar ones, which can be problematic in protein design (Jaramillo and Wodak, 2005).…”