title: Free Energy Perturbation Calculation of Relative Binding Free Energy between Broadly Neutralizing Antibodies and the gp120 Glycoprotein of HIV-1.
abstract: 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, 0.68kcal/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, R2=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.
authors.affiliation: Department of Chemistry, Columbia University, 3000 Broadway, MC 3178, New York, NY 10027, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Clark
authors.affiliation: Department of Pathology, Columbia University Medical Center, 630 W. 168th St, New York, NY 10032, USA.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Gindin
authors.affiliation: Vaccine Research Center, NIAID, National Institutes of Health, 40 Convent Drive, Bethesda, MD 20892, USA.
authors.forename: Baoshan
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Schrodinger Inc., 120 W 45th Street, New York, NY 10036, USA.
authors.forename: Lingle
authors.initials: L
authors.lastname: Wang
authors.affiliation: Schrodinger Inc., 120 W 45th Street, New York, NY 10036, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Abel
authors.affiliation: Department of Chemistry, Columbia University, 3000 Broadway, MC 3178, New York, NY 10027, USA.
authors.forename: Colleen S
authors.initials: CS
authors.lastname: Murret
authors.affiliation: Department of Chemistry, Columbia University, 3000 Broadway, MC 3178, New York, NY 10027, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Xu
authors.affiliation: Vaccine Research Center, NIAID, National Institutes of Health, 40 Convent Drive, Bethesda, MD 20892, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Bao
authors.affiliation: Vaccine Research Center, NIAID, National Institutes of Health, 40 Convent Drive, Bethesda, MD 20892, USA.
authors.forename: Nina J
authors.initials: NJ
authors.lastname: Lu
authors.affiliation: Vaccine Research Center, NIAID, National Institutes of Health, 40 Convent Drive, Bethesda, MD 20892, USA.
authors.forename: Tongqing
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry and Biophysics, Columbia University Medical Center, 701 West 168th Street, New York, NY 10032, USA; Vaccine Research Center, NIAID, National Institutes of Health, 40 Convent Drive, Bethesda, MD 20892, USA.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.affiliation: Department of Biochemistry and Biophysics, Columbia University Medical Center, 701 West 168th Street, New York, NY 10032, USA; Vaccine Research Center, NIAID, National Institutes of Health, 40 Convent Drive, Bethesda, MD 20892, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Shapiro
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Center for Computational Biology and Bioinformatics, Department of Systems Biology, Department of Medicine, Howard Hughes Medical Institute, Columbia University, 1130 Street Nicholas Avenue, Room 815, New York, NY 10032, USA.
authors.forename: Barry
authors.initials: B
authors.lastname: Honig
authors.affiliation: Department of Chemistry, Columbia University, 3000 Broadway, MC 3178, New York, NY 10027, USA. Electronic address: raf8@columbia.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Friesner
mesh_terms: D057134:Antibodies, Neutralizing / Q000737:chemistry* / Q000378:metabolism*; D019295:Computational Biology; D015483:HIV Antibodies / Q000737:chemistry* / Q000378:metabolism*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D020349:Surface Plasmon Resonance; D013816:Thermodynamics
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; C514793:gp120 protein, Human immunodeficiency virus 1
keywords: alchemical FEP; binding affinity optimization; computational chemistry; physics-based models; protein structure prediction