The interplay of sequence and stereochemistry in defining conformation in proteins and polypeptides

Abstract

Sequential specification of conformation in proteins and polypeptides is a triangular interplay involving the system of linked peptides, the sequences in side chains, and water as solvent. Stereochemistry in side chain linkages is obviously important in the interaction between all of the players, but no specification of its explicit role, if any, in linking sequence with conformation has been made. Flory and coworkers made a puzzling observation in 1967 that, when mutated from poly-L to alternating-L,D stereochemical structure, polypeptides will suffer a reduction in overall dimension or characteristic ratio by an astonishing factor of 10 and to a value even lower than that predicted for free rotation (Miller, W. G.; Brant, D. A.; Flory, P. J. J Mol Biol 1967, 23, 67-80). Enquiring into this longstanding puzzle, Durani and coworkers found that the stereochemical modification will also abolish conformational sensitivity in polypeptide structure to solvent, because electrostatic interactions in the system of linked peptides are transformed from a condition of mutual conflict to one of harmony (Ramakrishnan, V.; Ranbhor, R.; Kumar, A.; Durani, S. J Phys Chem B 2006, 110, 9314-9323). Thus, poly-L stereochemistry could be the fulcrum linking sequences with phi,psis in protein and polypeptide structures, via dielectric arbitrations in a conflicting type of interpeptide electrostatics, in agreement with the electrostatic screening model of Avbelj and Moult (Avbelj, F.; Moult, J. Biochemistry 1995, 34, 755-764).