CONFORMATIONAL EQUILIBRIA OF VALINE STUDIED BY DYNAMICS SIMULATION

The conformational probability distribution of a valine residue in the valine dipeptide and of the valine side chain in an alpha-helix, as well as the change in helix stability for replacing alanine with valine, has been calculated by molecular dynamics simulations of explicitly hydrated systems: dipeptide, tetrapeptide and 10-, 14- and 18-residue oligo-alanine helices. All computed free-energy differences are means from at least eight separate slow-growth simulations, four in each direction and are reported with their root-mean-square devia0tions. Different values for the change in free energy of folding (DELTA-DELTA-G-degrees) have been calculated with the use of forcefields having an all-atom and a central-atom representation of methyl groups, etc. The value obtained with the all-atom forcefield agrees well with new experimental values (3 kj/mol = 0.7 kcal/mol). Furthermore, the most stable valine side-chain rotamer in the helix is different for these two representations. The most stable rotamer for the all atom conformation is the same one that predominates for valines in alpha-helices in proteins of known conformation. The lower conformational freedom of the valine side chain in the helix contributes 1 kJ/mol to the difference in stability computed with the all-atom potential; unfavorable interactions of the side chain with the helix, even in the most stable conformation, further increase DELTA-DELTA-G-degrees.