Paper Citing NAMD - Abstract
Emileh, Ali; Abrams, Cameron F.
A mechanism by which binding of the broadly neutralizing antibody b12 unfolds the inner domain alpha 1 helix in an engineered HIV-1 gp120
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 79:537-546, FEB 2011
Using all-atom simulations, we examine the role of the I109C/Q428C disulfide "stitch" in altering the conformational distribution of engineered HIV-1 gp120 core relevant for binding of the broadly neutralizing recombinant antibody b12. In particular, we propose that the I109C/Q428C stitch results in a conformational distribution favoring an unfolded inner-domain alpha 1-helix upon binding of b12. Using targeted molecular dynamics, we show that folded alpha 1 in the b12-bound conformation of gp120 is stable both with and without the stitch, but that with folded alpha 1, the stitch requires an orientation of the beta 20/beta 21 sheet that is sterically incompatible with b12 binding. Forcing beta 20/beta 21 into the orientation displayed by the b12-bound conformation after folding alpha 1 with the stitch intact results in partial unfolding of alpha 1, whereas without the stitch, beta 20/beta 21 reorientation does not affect the conformation of alpha 1. These findings collectively support the hypothesis that the disulfide stitch shifts the conformational distribution of alpha 1 to the unfolded state, meaning an unfolded alpha 1 is not a strict requirement of the b12-bound conformational ensemble of gp120's lacking the I109C/Q428C stitch. Proteins 2011; 79:537-546. (C) 2010 Wiley-Liss, Inc.
