Analysis on conformational stability of C-peptide of ribonuclease A in water using the reference interaction site model theory and Monte Carlo simulated annealing

Solvation structure and conformational stability of the C-peptide fragment of ribonuclease A in pure water have been analyzed using the full reference interaction site model (RISM) theory. The charged groups in the side chain s of Lys-1(+), Glu-2(-), Lys-7(+), Arg-10(+), and His-12(+) (in particular, the four like-charged groups) play substantial roles in stabilizing the co nformations. The solvation free energy and the conformational energy are go verned by the contribution from the electrostatic interaction with water an d the intramolecular Coulombic energy, respectively, and the conformational stability is determined by competition of these two factors. The contribut ions from the hydrophobic hydration and the van der Waals and torsion terms in the conformational energy are less important, which is in contrast to t he result for Met-enkephalin. The Monte Carlo simulated annealing combined with the RISM theory has been applied to the C-peptide using an almost full y extended conformation as the initial one. The conformation first changes in the direction that the charged groups in the side chains are more expose d to water, and in particular, the positively charged groups are closer tog ether. Thus, the solvation free energy decreases greatly in the initial sta ge. Although this leads to a significant increase in the intramolecular Cou lombic repulsion energy, the decrease in the solvation free energy dominate s. In the later stage, however, a further decrease in the solvation free en ergy gives rise to an even larger increase in the intramolecular Coulombic repulsion energy, and the conformational change is greatly decelerated. The conformations thus stabilized in four different runs of the combined progr am are quite similar. The peptide conformation in water is stabilized far m ore rapidly than in the gas phase. (C) 1999 American Institute of Physics. [S0021-9606(99)50808-8].