Peptide and Protein Structure Prediction with a Simplified Continuum Solvent Model

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.

Figure 1.

Atomic self-energies calculated for 810,675 non-polar-hydrogen atoms in high-resolution structures.

Figure 2.

Representative interactions illustrated in figure S1, as given by the parameters inferred from iterative refinement. The Glu-Arg interaction energy is plotted in red, Glu-Lys in blue, Glu-His in light blue, Gln-His in green, NMA-NMA in orange, and Phe-Phe in gray. For the five polar interactions, x represents the heavy-atom separation along a linear hydrogen bond. NMA = N-methyl acetamide.

Figure 3:. Energy landscapes and predicted native conformations for diverse set of model systems.

Left) Effective energy versus backbone deviation from experimental structure, for conformations sampled in simulations started from an extended conformation, for a) trp-zip 2, b) MBH12, c) U(1–17)T9D, d) BS1, e) trp-cage, and f) villin subdomain HP35. The extent of sampling is indicated by color, from red (most) to purple (least). Right) Centroid of the largest cluster of sampled structures (gold), superimposed on the experimental structure (green), shown as α-carbon traces. Structures were rendered using the programs MolScript and Raster3D.