Biophys J, August 2000, p. 646-655, Vol. 79, No. 2

Essential Motions and Energetic Contributions of Individual Residues in a Peptide Bound to an SH3 Domain

Jií Kolafa,^* John W. Perram, and Robert P. Bywater

 ^*E. Hála Laboratory of Thermodynamics, Institute of Chemical Process Fundamentals, Academy of Sciences, CZ-16502 Praha, Czech Republic,  Mærsk McKinney Møller Institute for Production Technology, University of Southern Denmarkmain campus Odense University, DK-5230 Odense M, and  Biostructure Group, Medicinal Chemistry, Novo Nordisk A/S, DK-2760 Måløv, Denmark

We have studied protein-ligand interactions by molecular dynamics simulations using software designed to exploit parallel computing architectures. The trajectories were analyzed to extract the essential motions and to estimate the individual contributions of fragments of the ligand to overall binding enthalpy. Two forms of the bound ligand are compared, one with the termini blocked by covalent derivatization, and one in the underivatized, zwitterionic form. The ends of the peptide tend to bind more loosely in the capped form. We can observe significant motions in the bound ligand and distinguish between motions of the peptide backbone and of the side chains. This could be useful in designing ligands, which fit optimally to the binding protein. We show that it is possible to determine the different contributions of each residue in a peptide to the enthalpy of binding. Proline is a major net contributor to binding enthalpy, in keeping with the known propensity for this family of proteins to bind proline-rich peptides.

Biophys J, August 2000, p. 646-655, Vol. 79, No. 2
© 2000 by the Biophysical Society   0006-3495/00/08/646/10  $2.00