A portion of the research was carried out at Brookhaven National Laboratory under the auspices of the U. S. Atomic Energy Commission. This work was also supported by the National Science Foundation.

A method is described for the inclusion of the effects of hydration in empirical conformational energy computations on polypeptides. The free energy of hydration is composed of additive contributions of various functional groups. The hydration of each group is assumed to be proportional to the accessible surface area of the group. The constants of proportionality, representing the free energy of hydration per unit area of accessible surface, have been evaluated for seven classes of groups (occurring in peptides) by least-squares fitting to experimental free energies of solution of small monofunctional aliphatic and aromatic molecules. The same method has also been applied to the modeling of the enthalpy and heat capacity ofhydration, each of which is computed from the accessible surface area.The free energy of folding of a protein consists of the sum of contributions from the energy of its intramolecular interactions (1, 2) and from the free energy of interaction of the molecule with the surrounding solvent water. Exact computation of the latter contribution still poses problems (3). As a practical approach, hydration-shell models have been used. In these models, the free energy of interaction of water molecules with the solute is expressed in the form of an averaged effective potential of interaction of atoms (and functional groups) of a solute molecule with a layer of solvent around each atom (4-10)-i.e., in terms ofa potential ofmean force (3). An empirical free energy of hydration is assigned to every atom and group. When the conformation of the protein changes, some water is eliminated from the hydration shell whenever groups on the protein approach each other. The free energy change accompanying this process depends on the total free energy of hydration of the groups and on the amount of water being eliminated from the hydration shells. This amount, in turn, depends on the size and distance of separation of the groups that approach each other, and it can be computed by geometrical methods from the volumes of overlapping spheres (4-6, 10, 11).The hydration-shell model contains several approximations, which may be sources of error and also reduce the speed of computer-based numerical computations (8), such as the thickness of the shell, the apportioning of the free energy between overlapping hydration shells of covalently connected atoms, and the calculation of the volume of overlap of three or more hydration spheres that belong to nearby atoms. The latter problem can be overcome, however, by modifying the computing procedures (10, 11).We have initiated an alternative approach, in order to avoid these problems. We assume that the extent of interaction of any functional group i of a solute with the solvent is proportional to the solvent-accessible surface area Ai of group i (12-14) because the group can interact directly only with the water molecules that are in contact with the group at this surface. Thus, the total free energy of hydration of a solute molecule is given by Eq. 1: AGh = E Ai [1] where...

Some of the parameters that are used in the computer program ECEPP (Empirical Conformational Energy Program for Peptides) to describe the geometry of amino acid residues and the potential energy of interactions have been updated. The changes are based on recently available experimental information. The most signifcant changes improve the geometry and the interactions of prolyl and hydroxyprolyl residues, on the basis of crystallographic structural data. The structure of the pyrrolidine ring has been revised to correspond to the experimentally determined extent of out-of-plane puckering of the five-membered ring. The geometry of the peptide group preceding a Pro residue has also been altered. The parameters for nonbonded interactions involving the C6 and H* atoms of Pro and Hyp have been modified. Use of the revised parameters provides improvements in the computed minimum-energy conformations of peptides containing the Pro-Pro and Ala-Pro sequences. In particular, it is demonstrated that an a-helix-like conformation of a residue preceding Pro is now only of moderately high energy, and thus it is an accessible state. This result corroborates the observed occurrence of Pro residues in kinked a-helices in globular proteins. The structure of the poly(G1y-PrePro) triple helix, a computational model for collagen structure, has been recomputed. The validity of previous computations for this model structure has been confirmed. The refinement of the computed interactions has provided a new general model structure to be used for future computations on collagen-like polypeptides.

Conformational energy calculations using ECEPP (Empirical Conformational Energy Program for Peptides) were carried out on the N-acetyl-N'-methylamides of the 20 naturally occurring amino acids. Minimum-energy conformations were located, and the relative conformational energy, librational entropy, and free energy each minimum were calculated. The effects of intrinsic torsional potentials, intramolecular hydrogen bonds, and librational entropy on relative conformational energies and locations of minima are discussed. The results are categorized most easily by use of a new conformational letter code that is introduced here.

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