Folding of the Villin Headpiece Subdomain from Random Structures. Analysis of the Charge Distribution as a Function of pH.

摘要

The structure of the 36 residue villin headpiece subdomain is investigated with the electrostatically driven Monte Carlo method. The ECEPP/3 (Empirical Conformational Energy Program for Peptides) force field, plus two different continuum solvation models, were used to describe the conformational energy of the chain with both blocked and unblocked N and C termini. A statistical analysis of an ensemble of ab initio generated conformations was carried out, based on a comparison with a set of ten native-like structures derived from published experimental data, by using rigid geometry and NMR-derived constraints obtained at pH 3.7. The ten native-like structures satisfy the NMR-derived constraints. The whole ensemble of conformations of the terminally unblocked villin headpiece sub-domain, generated by using ECEPP/3 with a continuum solvation model, were subsequently evaluated at pH 3.7 with a potential function that includes ECEPP/3 combined with a fast multigrid boundary element method. At pH 3.7, the lowest-energy conformation found during the conformational search satisfies approximately 70% of both the distance and the dihedral-angle constraints, and possesses the characteristic packing of three phenylalanine residues that constitute the main part of the hydrophobic core of the molecule. On the other hand, computations at pH 3.7 and pH 7.0 for the ten native-like structures satisfying the NMR-derived constraints indicate a substantial change in the charge distribution for each type of amino acid residue with the change in pH. The results of this study provide a basis to understand the effect of the interactions, such as hydrophobicity, charge-charge interaction and solvent polarization, on the stability of this small alpha-helical protein.