(653f) HIV-1 gp120 : Atomic Insight Into a Layered Topology and Plasticity of the Inner Domain

The HIV-1 envelope glycoprotein ?spike?, a trimer of gp120/gp41 heterodimers, uses poorly characterized conformational changes triggered by ordered binding to target cell receptors to drive viral/cell fusion and initiate infection. Based on the most recent crystallographic structure of the gp120 subunit [Pancera et al, PNAS 107:1166 (2010)], it has been speculated that an important part of this conformational change cascade is a ?layering? transition in the so-called inner domain (some 31 residues responsible in part for gp120/gp41 binding). However, in absence of an unliganded structure, details underlying such a mechanism are not easily inferred from available crystal structures, but could be of potential value in both understanding the structural biology of the HIV-1 and in the design of entry inhibitors and immunogens. We use the relatively new method of temperature accelerated molecular dynamics (TAMD) [Abrams and Vanden-Eijnden, PNAS 107:4961 (2010)] to perform target-blind conformational sampling of gp120 in all-atom, explicit water, molecular dynamics simulations. Beginning from the activated, receptor-bound conformation, we observe in several independent TAMD simulations, ?un-layered? conformations consistent with initial states in a putative layering mechanism. Of particular interest is the observation that the inner domain helices α1 and α5 maintain contact despite belonging to different layers, while α5 disintegrates from the outer domain, revealing possibly important epitopes. Such opening of the condensed activated structure of gp120 into a conformation displaying distinct layers leads to an increase in the solvent accessible surface area (SASA) of residues belonging to different conformational antibody epitopes that are buried in the activated structure, especially those involving layer 3. Also, the conformational search lead us to a structure within 2.1 A of the recently resolved, F015 bound crystal structure of gp120. It has to be noted that the F105-bound crystal structure lacks the gp41 interacting region whereas this region is available in our simulations. Our trajectories show a significant increase in the SASA of residues in layer 2 which recently have been found to be indirectly affecting the binding properties and gp41-association characteristics of gp120, but are buried in the available structures. These conformations generally show a very plastic inner domain with two independent layers (layers 1 and 2) which presumably contributes to the ?conformational masking? of conserved epitopes in gp120 and helps the virion particle escape immune surveillance. When this is present in the context of the viral spike, it makes targeting the glycoprotein extremely hard for large molecules like antibodies. Our produced conformations help to explain how the inner domain plasticity is materialized in an all-atom model and also clearly show the proposed layered structure of a presumably unliganded model of gp120.