title: Computational Refinement and Validation Protocol for Proteins with Large Variable Regions Applied to Model HIV Env Spike in CD4 and 17b Bound State.
abstract: Envelope glycoprotein gp120 of HIV-1 possesses several variable regions; their precise structure has been difficult to establish. We report a new model of gp120, in complex with antibodies CD4 and 17b, complete with its variable regions. The model was produced by a computational protocol that uses cryo-electron microscopy (EM) maps, atomic-resolution structures of the core, and information on binding interactions. Our model has excellent fit with EMD: 5020, is stereochemically and energetically favorable, and has the expected binding interfaces. Comparison of the ternary arrangement of the loops in this model with those bound to PGT122 and PGV04 suggested a possible motion of the V1V2 away from the CCR5 binding site and toward CD4. Our study also revealed that the CD4-bound state of the V1V2 loop is not optimal for gp120 bound with several neutralizing antibodies.
authors.affiliation: Computer Science Department, The University of Texas at Austin, 1 University Station, Austin, TX 78712, USA.
authors.forename: Muhibur
authors.initials: M
authors.lastname: Rasheed
authors.affiliation: Computer Science Department, The University of Texas at Austin, 1 University Station, Austin, TX 78712, USA.
authors.forename: Radhakrishna
authors.initials: R
authors.lastname: Bettadapura
authors.affiliation: Computer Science Department, The University of Texas at Austin, 1 University Station, Austin, TX 78712, USA. Electronic address: bajaj@cs.utexas.edu.
authors.forename: Chandrajit
authors.initials: C
authors.lastname: Bajaj
mesh_terms: D057134:Antibodies, Neutralizing / Q000378:metabolism; D015704:CD4 Antigens / Q000737:chemistry / Q000378:metabolism*; D020285:Cryoelectron Microscopy; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120