Molecular dynamics simulation of the DH270.6 and CH235.12 HIV-1 broadly neutralizing antibodies with the HIV-1 Envelope glycoprotein

Molecular dynamics simulation datasets for the DH270.6 (DH270.6_Trajectories.tar) and CH235.12 (CH235.12_Trajectories.tar) broadly neutralizing antibody (bnAb) variable domains interacting with HIV-1 antigen fragments derived from individuals CH848 and CH505. Datasets comprise 250 nanosecond simulations in Amber NetCDF format. These simulations were used to prepare Markov state models (MSMs) of the association between the variable domains and the antigen fragment from the unbound state. The MSMs were then used to identify key transition states in the association process that facilitate binding. To design vaccines capable of selecting specific antibody mutations from germline, we identified transition states that involved or could involve those mutations for design. We then modified the antigen such that introducing the target antibody mutation would result in a substantial increase in affinity with the designed antigen based on the transition state structure(s). We showed that this design approach was successful for two HIV-1 Envelope bnAbs targeting distinct epitopes and that immunization with the designed antigens resulted in enhanced selection of key, target antibody mutations. The MSMs built from these datasets were crucial for guiding this design approach and shed light on the difficult-to-observe structural states that characterize protein-protein interaction formation.