Ligand-dependent conformational dynamics of MPER-binding HIV-1 antibody Fab235.

Abstract

The glycoprotein gp160 of HIV-1 is targeted by many antibodies that differ in neutralizing capacity. Due to the high mutation rate of gp160, its relatively conserved membrane-proximal external region (MPER) is an important epitope for eliciting broadly neutralizing antibodies. However, the MPER is located underneath the gp160 ectodomain, making it difficult to access. Thus, the conformational property of the Fab domain of the antibody is likely a key factor in the binding to MPER and HIV-1 neutralization. As a test system, we use vaccine-elicited MPER antibody Fab235, to investigate its ligand-dependent conformational behavior by performing all-atom molecular dynamics simulations. We perform simulations with or without a bound MPER, 1-µs each. Compared to the APO state, the MPER-bound state had increased inter-domain contacts within Fab235 and attendant reduction in conformational fluctuation which propagated down to the constant domains, in particular to CH1. On the other hand, removing MPER from the MPER-bound structure led to reduction of inter-domain contacts and an increase in fluctuation of the CH1 domain, similar to the original APO structure. The compliance of Fab in the APO state may be beneficial for approaching and binding to the MPER, while stiffening upon binding to MPER would support interaction between the antibody and receptors on innate cells or complement proteins interacting via the Fc domain. Our results also indicate that ligand-dependent contacts between the variable and constant domains enable allosteric control of ligand binding.