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Protein side chain modeling with orientation-dependent atomic force fields derived by series expansions.

ABSTRACT: We describe the development of new force fields for protein side chain modeling called optimized side chain atomic energy (OSCAR). The distance-dependent energy functions (OSCAR-d) and side-chain dihedral angle potential energy functions were represented as power and Fourier series, respectively. The resulting 802 adjustable parameters were optimized by discriminating the native side chain conformations from non-native conformations, using a training set of 12,000 side chains for each residue type. In the course of optimization, for every residue, its side chain was replaced by varying rotamers, whereas conformations for all other residues were kept as they appeared in the crystal structure. Then, the OSCAR-d were multiplied by an orientation-dependent function to yield OSCAR-o. A total of 1087 parameters of the orientation-dependent energy functions (OSCAR-o) were optimized by maximizing the energy gap between the native conformation and subrotamers calculated as low energy by OSCAR-d. When OSCAR-o with optimized parameters were used to model side chain conformations simultaneously for 218 recently released protein structures, the prediction accuracies were 88.8% for ?(1) , 79.7% for ?(1 + 2) , 1.24 Å overall root mean square deviation (RMSD), and 0.62 Å RMSD for core residues, respectively, compared with the next-best performing side-chain modeling program which achieved 86.6% for ?(1) , 75.7% for ?(1 + 2) , 1.40 Å overall RMSD, and 0.86 Å RMSD for core residues, respectively. The continuous energy functions obtained in this study are suitable for gradient-based optimization techniques for protein structure refinement. A program with built-in OSCAR for protein side chain prediction is available for download at http://sysimm.ifrec.osaka-u.ac.jp/OSCAR/.

SUBMITTER: Liang S

PROVIDER: S-EPMC3072444 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Protein side chain modeling with orientation-dependent atomic force fields derived by series expansions.

Liang Shide S Zhou Yaoqi Y Grishin Nick N Standley Daron M DM

Journal of computational chemistry 20110304 8

We describe the development of new force fields for protein side chain modeling called optimized side chain atomic energy (OSCAR). The distance-dependent energy functions (OSCAR-d) and side-chain dihedral angle potential energy functions were represented as power and Fourier series, respectively. The resulting 802 adjustable parameters were optimized by discriminating the native side chain conformations from non-native conformations, using a training set of 12,000 side chains for each residue ty ...[more]

PMID: 21374632

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Project description:Protein structure modeling and prediction have important applications throughout the biological sciences, from the design of pharmaceuticals to the elucidation of enzyme mechanisms. At the core of most protein modeling is an energy function, the minimum of which represents the free energy "cost" for forming a correct protein structure. The most commonly used energy functions are knowledge-based statistical potential functions; that is, they are empirically derived from statistical analysis of a set of high-resolution protein structures. When that kind of potential function is constructed, the anisotropic orientation dependence between the interacting groups is a critical component for accurately representing key molecular interactions, such as those involved in protein side-chain packing. In the literature, however, many potential functions are limited in their ability to describe orientation dependence. In all-atom potentials, they typically ignore heterogeneous chemical-bond connectivity. In coarse-grained potentials, such as (semi)-residue-based potentials, the simplified representation of residues often reduces the sensitivity of the potential to side-chain orientation. Recently, in an effort to maximally capture the orientation dependence in side-chain interactions, a new type of all-atom statistical potential was developed: OPUS-PSP (potential derived from side-chain packing). The key feature of this potential is its explicit description of orientation dependence in molecular interactions, which is achieved with a basis set of 19 rigid-body blocks extracted from the chemical structures of 20 amino acid residues. This basis set is specifically designed to maximally capture the essential elements of orientation dependence in molecular packing interactions. The potential is constructed from the orientation-specific packing statistics of pairs of those blocks in a nonredundant structural database. On decoy set tests, OPUS-PSP significantly outperforms most of the existing knowledge-based potentials in terms of both its ability to recognize native structures and its consistency in achieving high Z scores across decoy sets. The application of OPUS-PSP to conformational modeling of side chains has led to another method, called OPUS-Rota. In terms of combined speed and accuracy, OPUS-Rota outperforms all of the other methods in modeling side-chain conformation. In this Account, we briefly outline the basic scheme of the OPUS-PSP potential and its application to side-chain modeling via OPUS-Rota. Future perspectives on the modeling of orientation dependence are also discussed. The computer programs for OPUS-PSP and OPUS-Rota can be downloaded at http://sigler.bioch.bcm.tmc.edu/MaLab . They are free for academic users.

Dataset Information

Protein side chain modeling with orientation-dependent atomic force fields derived by series expansions.

Publications

Protein side chain modeling with orientation-dependent atomic force fields derived by series expansions.

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