Computational Refinement and Validation Protocol for Proteins with Large Variable Regions Applied to Model HIV Env Spike in CD4 and 17b Bound State

• Our protocol had significant accuracy in scoring existing X-ray structures of gp120
• Reported gp120 model with all variable loops has excellent fit with EM map EMD: 5020
• Reported gp120 model is stereochemically and energetically favorable
• Structure suggests possible movement of the loops induced by binding with CD4 and 17b

SummaryEnvelope 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.

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