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J Phys Chem B. 2018 Dec 13;122(49):11355-11362. doi: 10.1021/acs.jpcb.8b07264. Epub 2018 Oct 5.

Peptide and Protein Structure Prediction with a Simplified Continuum Solvent Model.

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1
Center for Molecular Modeling, Center for Information Technology , National Institutes of Health , Bethesda , Maryland 20892 , United States.

Abstract

A continuum solvent model based on screened Coulomb potentials has been simplified and parametrized to sample native-like structures in replica-exchange simulations of each of six different peptides and miniproteins. Low-energy, native, and non-native structures were used to iteratively refine 11 parameter values. The centroid of the largest cluster of structures sampled in simulations initiated from an extended conformation represents the predicted structure. The main-chain rms deviation of this prediction from the experimental structure was 0.47 Å for the 12-residue Trp-zip2, 0.86 Å for the 14-residue MBH12, 2.53 Å for the 17-residue U(1-17)T9D, 2.03 Å for the 20-residue BS1, 1.08 Å for the 20-residue Trp-cage, and 3.64 Å for the 35-residue villin headpiece subdomain HP35. The centroid of the sixth largest cluster sampled for HP35 deviated by 0.91 Å. The CHARMM22/CMAP force field was used, with an additional ψ torsion term for residues other than glycine and proline. Six parameters govern the dielectric response of the continuum solvent, and four values of surface tension approximate nonpolar effects. An atom's self-energy and interaction energies are screened independently, each depending on whether the atom is part of a charged group, a neutral hydrogen-bonding main-chain group, or any other neutral group. The parameters inferred result in strong main-chain hydrogen bonds, consistent with the view that protein folding is dominated by the formation of these bonds. (1,2) Conformations of MBH12 and BS1 were excluded from the energy-function refinement, suggesting the parameters, referred to as SCP18, are transferable. An efficient estimate of solvent-accessible surface area is also described.

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