It is well established that the amino acid sequence of a protein determines how the protein folds, and whether the protein is destined to be water soluble or membrane-bound, and to which small molecules or other macromolecules the protein binds. However, the atomic basis of these events of molecular recognition is not yet understood well enough to permit many useful predictions from the knowledge of the amino acid sequence alone. This is unfortunate, because many advances in practical problems, such as drug and protein design, await further progress in understanding these relationships. This proposal takes three directions in addressing this central problem: (1) Crystal structure studies of small amphiphilic proteins and of designed proteins, to elucidate rules of protein folding, and rules for association of proteins with lipids and other apolar surfaces: (2) Computations of energies of protein-folding and protein-lipid association, using atomic solvation parameters, semi-empirical quantities that represent an atom-based solvation (or hydrophobic) free energy; and (3) Computational analysis of amino acid sequences, using extensions of the PROFILE method which is a way of representing information about families amino acid sequences in proteins.*** //
