Hybrid QM/MM study of a fundamental biological interaction surrounded by its protein environment

The three-dimensional structures of the antigen/antibody complexes of hen e gg white lysozyme with Fab HyHEL-5 and Fab D44.1 show a hydrophobic hole in their interface region, in which an interaction between the side-chains of two arginine residues from the lysozyme and two glutamic acids from the he avy chain of the Fab fragments is observed. In this work, the four interact ing residues were treated using a quantum mechanical method, and the rest o f the whole protein was handled with a molecular mechanics force field. Sli ght different conformations are adopted by the interacting system in the in terface region of both complexes. In addition, HyHEL-5 Fab/Lysozyme complex shows a preference to the formation of salt bridges between the glutamates and the arginines, whereas an interaction between neutral side-chains is e nergetically favorable in the D44.1 Fab/Lysozyme complex. The difference in enthalpic contributions obtained with these two distinct protonation state s can be responsible for the 1000-fold increase in the association constant of the HyHEL5 Fab/Lysozyme complex, when compared with the D44.1. Fab/Lyso zyme.