Influence of lysine content and pH on the stability of alanine-based copolypeptides

To account for the relative contributions of lysine and alanine residues to the stability of cu-helices of copolymers of these two residues, conformat ional energy calculations were carried our for several hexadecapeptides at several pHs. All the calculations considered explicitly the coupling betwee n the conformation of the molecule and the ionization equilibrium as a func tion of pH. The total free energy function used in these calculations inclu ded terms that account for the solvation free energy and free energy of ion ization. These terms were evaluated by means of a fast multigrid boundary e lement method. Reasonable agreement with experimental values was obtained f or the helix contents and vicinal coupling constants ((3)J(HN alpha)). The helix contents were found to depend strongly on the lysine content, in agre ement with recent experimental results of Williams et al. (Journal of the A merican Chemical Society. 1998, Vol. 120 pp. 11033-11043) In the lowest ene rgy conformation computed for a hexadecapeptide containing 3 lysine residue s at pH 6 the lysine side chains are preferentially hydrated; this decrease s the hydration of the backbone CO and NH groups. thereby forcing the latte r to form hydrogen bonds with each other in the helical conformation. The l owest energy conformation computed for a hexadecapeptide containing 6 lysin e residues at pH 6 show's a close proximity between the NH: groups of the l ysine side chains, a feature that was previously observed in calculations o f short alanine-based oligopeptides. The calculation on a blocked 16-mer of alanine shows a 7% helix content based on the Boltzmann averaged vicinal c oupling constants computed from the dihedral angles phi, consistent with pr evious experimental evidence on triblock copolymers containing a central bl ock of alanines, and with earlier theoretical calculations. (C) 2001 John W iley & Sons, Inc.