ESTIMATION OF CHANGES IN SIDE-CHAIN CONFIGURATIONAL ENTROPY IN BINDING AND FOLDING - GENERAL-METHODS AND APPLICATION TO HELIX FORMATION

Theoretical estimations of changes in side chain configurational entro py are essential for understanding the different contributions to the overall thermodynamic behavior of important biological processes like folding and binding. The configurational entropy of any given side cha in in any particular protein can be evaluated from the complete energy profile of the side chain. Calculations of the energy profiles can be performed using the side chain single bond dihedrals as the only inde pendent variables as long as the structures at each value of the dihed rals are allowed to relax through small changes in the valence bond an gles. The probabilities of different side chain conformers obtained fr om these energy profiles are very similar to the conformer populations obtained by analysis of side chain preferences in the proteins of the Protein Data Bank. Also, side chain conformational entropies obtained from the energy profiles agree extremely well with those obtained fro m the Protein Data Bank conformer populations. Changes in side chain c onfigurational entropy in binding and folding can be computed as diffe rences in conformational entropy because, in most cases, the frequency of the rotational oscillation around the energy minimum of any given conformer does not appear to change significantly in the reaction. Cha nges of side chain conformational entropy calculated in this way were compared with experimental values. The only available experimental dat a-the effect of side chain substitution on the stability of alpha-heli ces-were used for this comparison. The experimental values were correc ted to subtract the solvent contributions. This comparison yields an e xcellent agreement between calculated and experimental values, validat ing not only the theoretical estimates but also the separability of th e entropic contributions into configurational terms and solvation rela ted terms. (C) 1994 Wiley-Liss, Inc.