Theoretical study of arginine–carboxylate interactions A. Melo a , M.J. Ramos a, * , W. B. Floriano b , J.A.N.F Gomes a , J.F.R. Lea ˜o a , A.L. Magalha ˜es a , B. Maigret c , M. C. Nascimento d , N. Reuter c a CEQUP/Departamento de Quı ´mica, Faculdade de Cie ˆncias, Universidade do Porto, Rua do Campo Alegre, 687, 4150 Porto, Portugal b Centro de Ciencias Exatas, Departamento de Fisica, Universidade Federal do Espirito Santo, Av. Fernando Ferrari s|n, Goiabeiras, Vitoria, ES 29060-900, Brazil c Laboratoire de Chimie The ´orique UA CNRS 510, Universite ´ de Nancy I, Domaine Scientifique Victor Grignard B. P. 239, 54506 Vandoeuvre, les Nancy cedex, France d Instituto de Quimica, Departamento de Fisico-Quimica, Cidade Universitaria, CT Bloco A sala 412, Rio de Janeiro, RJ 21949-900, Brazil Abstract The importance of the guanidinium–carboxylate interactions has sprung from the observed salt bridges often present in biological systems involving the arginine–glutamate or arginine–aspartate side chains. The strength of these interactions has been explained on the basis of a great coulombic energy gain, due to the closeness of two charges of opposite sign and the occurrence of H-bond interactions. However, in some environments proton transfer, from guanidinium to carboxylate, can occur with the consequent annihilation of charge. In this work, both ab-initio (6-31G** and MP2/6-31G**) and semi-empirical (AM1) calculations were performed in vacuo on appropriate models, methylguanidinium –acetate and methylguanidine –acetic acid to simulate the zwitterionic and the neutral forms, respectively. The results obtained indicate that, in solvent-free hydro- phobic environments, the neutral form should be more stable than the zwitterionic one.  1999 Elsevier Science B.V. All rights reserved. Keywords: Arginine–carboxylate interactions; Conformational analysis; 6-31G**; MP2; Proton transfer 1. Introduction It is now currently accepted that the three-dimen- sional structure of proteins is directly related to their biological activity. Therefore, while the amino acid sequence of a particular protein has all the informa- tion needed to trigger the biological response, the protein conformation ensures an effective interaction within itself as well as with specific receptor sites. In reality, the interactions between terminal side chains of amino acids in proteins seem to be a determinant factor in the mechanisms of a wide variety of biological phenomena as, for example, the antigen/ antibody recognition and enzyme–substrate inter- actions [1–5]. In particular, those involving ionic groups of opposite charge are expected to be more important because it is generally assumed that their electrostatic contributions to the overall stabilization energy are essential. One special case of this type of interactions involves the guanidinium group of the arginine, which usually defines the binding site of a wide variety of enzymes whose substracts contain carboxyl or phosphate groups [6] and have been the subject of an extensive list of studies [7]. In fact, the occurrence of close interactions with the terminal group of the side chain of arginine is noteworthy, and about 40% of the pairs of ionic groups within Journal of Molecular Structure (Theochem) 463 (1999) 81–90 0166-1280/99/$ - see front matter  1999 Elsevier Science B.V. All rights reserved. PII: S0166-1280(98)00396-0 * Corresponding author.