Role of electrostatic screening in determining protein main chain conformational preferences

Amino acids display significant variation in propensity for the alpha R-helical, beta-sheet, and other main chain conformational states in proteins and peptides. The physical reason for these preferences remains controversial. Conformational entropy, steric factors, and the hydrophobic effect have all been advanced as the dominant underlying cause. In this work, we explore the role of a fourth factor, electrostatics, in determining the main chain conformation in protein molecules. Potentials of mean force derived from experimental protein structures are used to evaluate the free energy of electrostatic and other interactions of a residue in a protein environment. The local and nonlocal electrostatic interactions of main chain polar atoms are found to be crucial for determining the preferences of residues for the alpha R-helical state and other main chain conformational states of a residue. Further, the strength of local and nonlocal electrostatic interactions is shown to depend on the electrostatic screening by solvent and protein groups. Residue specific modulation of this screening in a manner related to side chain bulk and squatness produces a model that fits the observed distribution of residue conformations in proteins and recent experimental mutagenesis data on protein stability better than any other single factor.