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What is the best reference state for designing statistical atomic potentials in protein structure prediction?

ABSTRACT: Many statistical potentials were developed in last two decades for protein folding and protein structure recognition. The major difference of these potentials is on the selection of reference states to offset sampling bias. However, since these potentials used different databases and parameter cutoffs, it is difficult to judge what the best reference states are by examining the original programs. In this study, we aim to address this issue and evaluate the reference states by a unified database and programming environment. We constructed distance-specific atomic potentials using six widely-used reference states based on 1022 high-resolution protein structures, which are applied to rank modeling in six sets of structure decoys. The reference state on random-walk chain outperforms others in three decoy sets while those using ideal-gas, quasi-chemical approximation and averaging sample stand out in one set separately. Nevertheless, the performance of the potentials relies on the origin of decoy generations and no reference state can clearly outperform others in all decoy sets. Further analysis reveals that the statistical potentials have a contradiction between the universality and pertinence, and optimal reference states should be extracted based on specific application environments and decoy spaces.

SUBMITTER: Deng H

PROVIDER: S-EPMC3409322 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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What is the best reference state for designing statistical atomic potentials in protein structure prediction?

Deng Haiyou H Jia Ya Y Wei Yanyu Y Zhang Yang Y

Proteins 20120618 9

Many statistical potentials were developed in last two decades for protein folding and protein structure recognition. The major difference of these potentials is on the selection of reference states to offset sampling bias. However, since these potentials used different databases and parameter cutoffs, it is difficult to judge what the best reference states are by examining the original programs. In this study, we aim to address this issue and evaluate the reference states by a unified database ...[more]

PMID: 22623012

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Project description:BACKGROUND: Accurate description of protein interaction with aqueous solvent is crucial for modeling of protein folding, protein-protein interaction, and drug design. Efforts to build a working description of solvation, both by continuous models and by molecular dynamics, yield controversial results. Specifically constructed knowledge-based potentials appear to be promising for accounting for the solvation at the molecular level, yet have not been used for this purpose. RESULTS: We developed original knowledge-based potentials to study protein hydration at the level of atom contacts. The potentials were obtained using a new Monte Carlo reference state (MCRS), which simulates the expected probability density of atom-atom contacts via exhaustive sampling of structure space with random probes. Using the MCRS allowed us to calculate the expected atom contact densities with high resolution over a broad distance range including very short distances. Knowledge-based potentials for hydration of protein atoms of different types were obtained based on frequencies of their contacts at different distances with protein-bound water molecules, in a non-redundant training data base of 1776 proteins with known 3D structures. Protein hydration sites were predicted in a test set of 12 proteins with experimentally determined water locations. The MCRS greatly improves prediction of water locations over existing methods. In addition, the contribution of the energy of macromolecular solvation into total folding free energy was estimated, and tested in fold recognition experiments. The correct folds were preferred over all the misfolded decoys for the majority of proteins from the improved Rosetta decoy set based on the structure hydration energy alone. CONCLUSION: MCRS atomic hydration potentials provide a detailed distance-dependent description of hydropathies of individual protein atoms. This allows placement of water molecules on the surface of proteins and in protein interfaces with much higher precision. The potentials provide a means to estimate the total solvation energy for a protein structure, in many cases achieving a successful fold recognition. Possible applications of atomic hydration potentials to structure verification, protein folding and stability, and protein-protein interactions are discussed.

Project description:BackgroundMultibody potentials accounting for cooperative effects of molecular interactions have shown better accuracy than typical pairwise potentials. The main challenge in the development of such potentials is to find relevant structural features that characterize the tightly folded proteins. Also, the side-chains of residues adopt several specific, staggered conformations, known as rotamers within protein structures. Different molecular conformations result in different dipole moments and induce charge reorientations. However, until now modeling of the rotameric state of residues had not been incorporated into the development of multibody potentials for modeling non-bonded interactions in protein structures.ResultsIn this study, we develop a new multibody statistical potential which can account for the influence of rotameric states on the specificity of atomic interactions. In this potential, named "rotamer-dependent atomic statistical potential" (ROTAS), the interaction between two atoms is specified by not only the distance and relative orientation but also by two state parameters concerning the rotameric state of the residues to which the interacting atoms belong. It was clearly found that the rotameric state is correlated to the specificity of atomic interactions. Such rotamer-dependencies are not limited to specific type or certain range of interactions. The performance of ROTAS was tested using 13 sets of decoys and was compared to those of existing atomic-level statistical potentials which incorporate orientation-dependent energy terms. The results show that ROTAS performs better than other competing potentials not only in native structure recognition, but also in best model selection and correlation coefficients between energy and model quality.ConclusionsA new multibody statistical potential, ROTAS accounting for the influence of rotameric states on the specificity of atomic interactions was developed and tested on decoy sets. The results show that ROTAS has improved ability to recognize native structure from decoy models compared to other potentials. The effectiveness of ROTAS may provide insightful information for the development of many applications which require accurate side-chain modeling such as protein design, mutation analysis, and docking simulation.

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What is the best reference state for designing statistical atomic potentials in protein structure prediction?

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What is the best reference state for designing statistical atomic potentials in protein structure prediction?

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