A molecular mechanics/continuum reaction field investigation of the interactions between polar amino acid side chains in water and organic solvents

Abstract

AbstractAn integrated procedure that computes in a consistent way both the intermolecular interaction energies and the solvation energies is reported. It interfaces the Sum of Interactions Between Fragments Ab initio computed molecular mechanics and the Langlei–Claverie continuum reaction field procedures. These two methodologies formulate the interaction energy as a sum of separate electrostatic, polarization, dispersion, and repulsion terms; the first two are computed with the help of distributed charges, dipoles, and quadrupoles derived from the ab initio SCF or MP2 molecular wave fundctions of individual solutes. This computational procedure will be used to estimate the solvent contribution to the interaction energy between polar amino acids side chains. We will consider, on the one hand, the terminal fragments of the side chains of aspartate and glutamate—namely the acetate anion and its protonated counterpart, acetic acid—and on the other hand, the terminal fragments of the cationic residues lysine, histidinium, and arginine, as represented by methylammonium, imidazolium, and methylguanidinium cations, respectively. The deprotonated counterpart of imidazolium, imidazole, is also investigated. With water as a solvent, and for each of the three anion‐cation complexes investigated, the total energy value DE (intermolecular + solvation) of the associated ion pair is only slightly larger (≈ 5 kcal/mol out of ≈ 170) than that of the fully dissociated arrangement and has a virtually flat dependence as a function of intermolecular separation. The associated complex has an enhanced stability in DMSO, a trend accented in chloroform and carbon tetrachloride. In water, the acetic acid–imidazole complex is less than 1 kcal/mol more stable than the dissociated pair. Energy balances, taking into account the experimental values of protonation energies of acetate and imidazole, indicate that the acetate‐imidazolium complex is more stable than its nonzwitterionic counterpart, acetic acid‐imidazole in water. In carbon tetrachloride, by contrast, the two complexes are of similar stabilities in terms of internal energies. When we consider free instead of internal energies of solvation, the three organic solvents stabilize the complex between the neutral molecules. The investigation of the interaction of two methylguanidiniums in the polar solvents suggests that the solvation energy of a complex, larger than that of the two isolated entities, could be able to overcome their electrostatic repulsion. This results in a small preference in favor of the complex. Implications of the findings of this study, and future prospects of applications to molecular recognition and conformational studies of oligopeptides and possibly proteins, are discussed. © 1995 John Wiley & Sons, Inc.