A COMPARISON OF 3 THEORETICAL APPROACHES TO THE STUDY OF SIDE-CHAIN INTERACTIONS IN PROTEINS

The continuing increase in the number of high-quality protein crystal structures means that a considerable amount of data is now available t o those studying the interactions of side-chain atoms. These experimen tal data can be used as a benchmark for theoretical studies of the spa tial distributions of side-chain-atom and side-chain-side-chain intera ctions. We use the program suite SIRIUS to calculate experimental side -chain-atom distributions, complementing the existing side-chain-side- chain distributions, for each of four systems: phenylalanine-carboxyla te, phenylalanine-aromatic, arginine-carboxylate, and arginine-aromati c. Three theoretical methods are tested: first the drug design program GRID, which is suited to calculating side-chain-atom distributions, s econdly the distributed multipole analysis (DMA) electrostatic approac h, and thirdly the empirical potential CHARMm. We look at the predicti ons of each method for the four systems, and compare theory with exper iment. Our results show that the strongly hydrogen-bonded arginine-car boxylate interaction is relatively easy to model, but that proper desc ription of aromatic systems requires an explicit representation of the pi-electrons, as modelled by the atomic quadrupoles in DMA. For argin ine-aromatic, we have to consider the effect of competing interactions before we can successfully reconcile experiment with theory.