Free Energy Perturbation Calculation of Relative Binding Free Energy between Broadly Neutralizing Antibodies and the gp120 Glycoprotein of HIV-1

JOURNAL OF MOLECULAR BIOLOGY

卷:429

Article

Clark, Anthony J.¹  Gindin, Tatyana⁶  Zhang, Baoshan³  Wang, Lingle⁴  Abel, Robert⁴  Murret, Colleen S.¹  Xu, Fang¹  Bao, Amy³  Lu, Nina J.³  Zhou, Tongqing³  Kwong, Peter D.^2,3  Shapiro, Lawrence^2,3  Honig, Barry⁵  Friesner, Richard A.¹ 

[1] Columbia Univ, Dept Chem, 3000 Broadway,MC 3178, New York, NY 10027 USA

[2] Columbia Univ, Dept Biochem & Biophys, Med Ctr, 701 West 168th St, New York, NY 10032 USA

[3] NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr, Bethesda, MD 20892 USA

[4] Schrodinger Inc, 120 W 45th St, New York, NY 10036 USA

[5] Columbia Univ, Dept Biochem & Mol Biophys, Ctr Computat Biol & Bioinformat, Dept Syst Biol,Dept Med,Howard Hughes Med Inst, 1130 St Nicholas Ave,Room 815, New York, NY 10032 USA

[6] Columbia Univ, Med Ctr, Dept Pathol, 630 W 168th St, New York, NY 10032 USA

DOI  :  10.1016/j.jmb.2016.11.021

来源: Elsevier

【 摘 要 】

Direct calculation of relative binding affinities between antibodies and antigens is a long-sought goal. However, despite substantial efforts, no generally applicable computational method has been described. Here, we describe a systematic free energy perturbation (FEP) protocol and calculate the binding affinities between the gp120 envelope glycoprotein of HIV-1 and three broadly neutralizing antibodies (bNAbs) of the VRC01 class. The protocol has been adapted from successful studies of small molecules to address the challenges associated with modeling protein protein interactions. Specifically, we built homology models of the three antibody gp120 complexes, extended the sampling times for large bulky residues, incorporated the modeling of glycans on the surface of gp120, and utilized continuum solvent-based loop prediction protocols to improve sampling. We present three experimental surface plasmon resonance data sets, in which antibody residues in the antibody/gp120 interface were systematically mutated to alanine. The RMS error in the large set (55 total cases) of FEP tests as compared to these experiments, 0.68 kcal/mol, is near experimental accuracy, and it compares favorably with the results obtained from a simpler, empirical methodology: The correlation coefficient for the combined data set including residues with glycan contacts, R-2 = 0.49, should be sufficient to guide the choice of residues for antibody optimization projects, assuming that this level of accuracy can be realized in prospective prediction. More generally, these results are encouraging with regard to the possibility of using an FEP approach to calculate the magnitude of protein protein binding affinities. (C) 2016 The Authors. Published by Elsevier Ltd.

【 授权许可】

Free