Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
Molecular Dynamics Simulations of the Structure of Human Antibody 10E8 Fab in Complex with Membrane-Proximal External Region of the HIV-1 GP41 Protein
10E is one of the most broadly and potently neutralizing HIV-1 antibodies known - it has been shown to neutralize ≈ 98 % of the tested viruses (Huang et al., 2012). To explore the mechanism of HIV-1 neutralization by 10E8 and thus obtain valuable information for vaccine and drug design, molecular dynamics (MD) simulations and binding free energy calculations were performed for crystal structure of 10E8 Fab in complex with its gp41 membrane-proximal external region (MPER) epitope (Huang et al., 2012).
The 60 ns MD simulations were carried out by the Amber 11 computer package using the Amber ff10 force field (Case et al., 2010). The MM-PBSA method (Massova & Kollman, 1999) was used to calculate the binding free energy and to analyze the binding interaction in detail. The ptraj procedure associated with AMBER 11 (Case et al., 2010) was used to identify hydrogen bonds in the dynamic structures of the complex of interest.
Analysis of the MD structures indicated that intermolecular hydrogen bonds and van der Waals interactions dominate the binding of gp41 and 10E8. In particular, the MD structures expose intermolecular hydrogen bonds involving such functionally important and highly conserved residues of gp41 as Trp-672 and Arg-683 (Huang et al., 2012). By decomposing the binding free energy into the contribution from each residue, the binding hot spots for 10E8 and gp41 were identified. For 10E8, the heavy chain residues Tyr-99, Asp-100, Phe-100a and Trp-100b provide significant contributions. For gp41, the residues Trp-672, Phe-673 and Arg-683 were identified as hotspots, in agreement with the data on alanine scanning, structural analysis and paratope analysis (Huang et al., 2012).
The data obtained in this study provide some useful insights that should aid the design of vaccines and small molecule inhibitors to neutralize HIV-1.
Huang, J., Ofek, G., Laub, L., Louder, M.K., Doria-Rose, N.A., Longo, N.S., Imamichi, H., Bailer, R.T., Chakrabarti, B., Sharma, S.K., Alam, S.M., Wang, T., Yang, Y., Zhang, B., Migueles, S.A., Wyatt, R., Haynes, B.F., Kwong, P.D., Mascola, J.R., Connors, M. (2012). Broad and potent neutralization of HIV-1 by a gp41-specific human antibody. Nature, 491(7424), 406-412.
Massova, I. & Kollman, P.A. (1999). Computational alanine scanning to probe protein-protein interactions: a novel approach to evaluate binding free energies. Journal of the American Chemical Society, 121, 8133-8143.
Ivan A. Kashyn 1
1 Institute of Bioorganic Chemistry