Critical role of anisotropy for the dimerization energies of two protein-protein recognition motifs: cis-N-methylacetamide versus a beta-sheet conformer of alanine dipeptide. A joint ab initio, density functional theory, andmolecular mechanics investigation

The dimerization energies of formamide and cis-N-methylacetamide (cis-NMA) are compared with those of the Ala and Gly dipeptides in their canonical be ta-sheet conformations using ab initio (SCF and MP2), density functional th eory (DFT), and the SIBFA molecular mechanics procedure. Consistent with th e gasphase ab initio and DFT results, the SIBFA procedure is able to accoun t for the larger dimerization energies of formamide and cis-NMA than of the dipeptides. In contrast, the majority of "conventional" force fields produ ced an inversion of the relative dimerization energies, giving rise to a mo re favorable dimerization of the Ala dipeptide than of cis-NMA (Beachy, M. D.; et al. J. Am. Chem. Sac. 1997, 119, 5908). Energy decomposition analysi s on the dimers of formamide and the Gly dipeptide shows the Coulombic ener gy contribution to be the most important term favoring the formamide dimer. The analysis based on the SIBFA procedure similarly;shows the multipolar e nergy term (E-MTP) to be the most important contributor to this difference. This is due to its monopole-dipole and monopole-quadrupole components. The issue of the transferability of the multipolar expansion is discussed in t he context of simulations of oligopeptides.