CONSERVATIVE AND NONCONSERVATIVE MUTATIONS IN PROTEINS - ANOMALOUS MUTATIONS IN A TRANSPORT RECEPTOR ANALYZED BY FREE-ENERGY AND QUANTUM-CHEMICAL CALCULATIONS

Experimental studies on a bacterial sulfate receptor have indicated an omalous relative binding affinities for the mutations Ser(130)-->Cys, Ser(130)-->Gly, and Ser(130)-->Ala. The loss of affinity for sulfate i n the former mutation was previously attributed to a greater steric ef fect on the part of the Cys side chain relative to the Ser side chain, whereas the relatively small loss of binding affinity for the latter two mutations was attributed to the loss of a single hydrogen bond. In this report we present quantum chemical and statistical thermodynamic studies of these mutations. Qualitative results from these studies in dicate that for the Ser(130)-->Cys mutation the large decrease in bind ing affinity is in part caused by steric effects, but also significant ly by the differential work required to polarize the Cys thiol group r elative to the Ser hydroxyl group. The Gly mutant cobinds a water mole cule in the same location as the Ser side chain resulting in a relativ ely small decrease in binding affinity. Results for the Ala mutant are in disagreement with experimental results but are likely to be limite d by insufficient sampling of configuration space due to physical cons traints applied during the simulation.