DETERMINATION OF THE STABLE MICROSTATES OF A PEPTIDE FROM NOE DISTANCE CONSTRAINTS AND OPTIMIZATION OF ATOMIC SOLVATION PARAMETERS

A methodology for analyzing nuclear Overhauser effect (NOE) data of in terconverting microstates of a peptide has been suggested recently, wh ich is based on pure statistical mechanical considerations. Thus, the mast stable microstates nd their populations are determined from the f ree energies, The success of this approach depends on the existence of a reliable potential energy function for the solvated peptide, in whi ch the solvent is treated implicitly. Such a potential is developed he re based on the stable structures of the cyclic hexapeptide cyclo(D-Pr o(1)-Phe(2)-Ala(3)-Ser(4)-Phe(5)-Phe(6)) in DMSO obtained by Kessler e t al. (J. Am. Chem. Soc. 1992, 114, 4805-4818) from NOE distance const raints, This study suggests that two different backbone motifs coexist in equilibrium, one with a beta I turn and the other with a beta II t urn around Ser(4)-Phe(5). We have first reconfirmed these findings by a best-fit analysis applied to a large set of energy-minimized structu res generated by our ''local torsional deformations'' (LTD) method, us ing the GROMOS force field with and without NOE distance restraints. H owever, the GROMOS energy E-GRO, which excludes solvent interactions w as found inappropriate to describe this sq;stem because the lowest ene rgy structures representing the beta I and pll motifs ,Ire similar to 15 and 5 kcal/mol above the global energy minimum, respectively. Solve nt effects are taken into account through E-tot = E-GRO + Sigma A(i) s igma(j), where A(i) is the solvent accessible surface area (SASA) of a tom i and sigma(i) is the atomic solvation parameter (ASP). We optimiz e the ASPs for DMSO by requiring that the E-tot values of beta I and e rr structures become the lowest globally, this is verified by an exten sive application of LTD. The set of ASPs obtained-here will be refined in the next work where free energy (rather than energy) consideration s will be taken into account. This salvation model, which is relativel y easy to handle, requires significantly less computer time than expli cit models of salvation and can readily be used in structural analysis of experimental data using GROMOS. The proposed derivation opens the way for the development of similar solvation models for peptides in ot her solvents, ASPs for rotein in water can be obtained by applying our methodology to surface Loops in proteins. Preliminary results for the ASPs, which are slightly different from the present values, were publ ished in a recent Letter.