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An all-atom force field for tertiary structure prediction of helical proteins.

ABSTRACT: We have developed an all-atom free-energy force field (PFF01) for protein tertiary structure prediction. PFF01 is based on physical interactions and was parameterized using experimental structures of a family of proteins believed to span a wide variety of possible folds. It contains empirical, although sequence-independent terms for hydrogen bonding. Its solvent-accessible surface area solvent model was first fit to transfer energies of small peptides. The parameters of the solvent model were then further optimized to stabilize the native structure of a single protein, the autonomously folding villin headpiece, against competing low-energy decoys. Here we validate the force field for five nonhomologous helical proteins with 20-60 amino acids. For each protein, decoys with 2-3 A backbone root mean-square deviation and correct experimental Cbeta-Cbeta distance constraints emerge as those with the lowest energy.

SUBMITTER: Herges T

PROVIDER: S-EPMC1304781 | biostudies-literature | 2004 Nov

REPOSITORIES: biostudies-literature

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An all-atom force field for tertiary structure prediction of helical proteins.

Herges T T Wenzel W W

Biophysical journal 20041101 5

We have developed an all-atom free-energy force field (PFF01) for protein tertiary structure prediction. PFF01 is based on physical interactions and was parameterized using experimental structures of a family of proteins believed to span a wide variety of possible folds. It contains empirical, although sequence-independent terms for hydrogen bonding. Its solvent-accessible surface area solvent model was first fit to transfer energies of small peptides. The parameters of the solvent model were th ...[more]

PMID: 15507688

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Project description:BACKGROUND: Although experimental methods for determining protein structure are providing high resolution structures, they cannot keep the pace at which amino acid sequences are resolved on the scale of entire genomes. For a considerable fraction of proteins whose structures will not be determined experimentally, computational methods can provide valuable information. The value of structural models in biological research depends critically on their quality. Development of high-accuracy computational methods that reliably generate near-experimental quality structural models is an important, unsolved problem in the protein structure modeling. RESULTS: Large sets of structural decoys have been generated using reduced conformational space protein modeling tool CABS. Subsequently, the reduced models were subject to all-atom reconstruction. Then, the resulting detailed models were energy-minimized using state-of-the-art all-atom force field, assuming fixed positions of the alpha carbons. It has been shown that a very short minimization leads to the proper ranking of the quality of the models (distance from the native structure), when the all-atom energy is used as the ranking criterion. Additionally, we performed test on medium and low accuracy decoys built via classical methods of comparative modeling. The test placed our model evaluation procedure among the state-of-the-art protein model assessment methods. CONCLUSION: These test computations show that a large scale high resolution protein structure prediction is possible, not only for small but also for large protein domains, and that it should be based on a hierarchical approach to the modeling protocol. We employed Molecular Mechanics with fixed alpha carbons to rank-order the all-atom models built on the scaffolds of the reduced models. Our tests show that a physic-based approach, usually considered computationally too demanding for large-scale applications, can be effectively used in such studies.

Project description:We present an extension of the CHARMM hexopyranose monosaccharide additive all-atom force field to enable modeling of glycosidic-linked hexopyranose polysaccharides. The new force field parameters encompass 1?1, 1?2, 1?3, 1?4, and 1?6 hexopyranose glycosidic linkages, as well as O-methylation at the C(1) anomeric carbon, and are developed to be consistent with the CHARMM all-atom biomolecular force fields for proteins, nucleic acids, and lipids. The parameters are developed in a hierarchical fashion using model compounds containing the key atoms in the full carbohydrates, in particular O-methyl-tetrahydropyran and glycosidic-linked dimers consisting of two molecules of tetrahyropyran or one of tetrahydropyran and one of cyclohexane. Target data for parameter optimization include full two-dimensional energy surfaces defined by the ?/? glycosidic dihedral angles in the disaccharide analogs as determined by quantum mechanical MP2/cc-pVTZ single point energies on MP2/6-31G(d) optimized structures (MP2/cc-pVTZ//MP2/6-31G(d)). In order to achieve balanced, transferable dihedral parameters for the ?/? glycosidic dihedral angles, surfaces for all possible chiralities at the ring carbon atoms involved in the glycosidic linkages are considered, resulting in over 5000 MP2/cc-pVTZ//MP2/6-31G(d) conformational energies. Also included as target data are vibrational frequencies, pair interaction energies and distances with water molecules, and intramolecular geometries including distortion of the glycosidic valence angle as a function of the glycosidic dihedral angles. The model-compound optimized force field parameters are validated on full disaccharides through comparison of molecular dynamics results to available experimental data. Good agreement is achieved with experiment for a variety of properties including crystal cell parameters and intramolecular geometries, aqueous densities, and aqueous NMR coupling constants associated with the glycosidic linkage. The newly-developed parameters allow for the modeling of linear, branched, and cyclic hexopyranose glycosides both alone and in heterogenous systems including proteins, nucleic acids and/or lipids when combined with existing CHARMM biomolecular force fields.

Dataset Information

An all-atom force field for tertiary structure prediction of helical proteins.

Publications

An all-atom force field for tertiary structure prediction of helical proteins.

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