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.

针对DH270.6（DH270.6_Trajectories.tar）和CH235.12（CH235.12_Trajectories.tar）两种广泛中和抗体（bnAb）可变区与来自个体CH848和CH505的HIV-1抗原片段相互作用的分子动力学模拟数据集。这些数据集包含了250纳秒的Amber NetCDF格式模拟。通过这些模拟，构建了描述可变区与抗原片段在非结合状态下相互作用的马尔可夫状态模型（MSM）。随后，利用这些MSM识别了促进结合的关键转换态。为了设计能够从亲本库中选择特定抗体突变的疫苗，我们确定了涉及或可能涉及这些突变的转换态进行设计。随后，我们对抗原进行了修改，使得引入目标抗体突变能够基于转换态结构显著增加与设计抗原的亲和力。我们证明了这种设计方法对于两种靶向不同表位的HIV-1包膜bnAb是成功的，并且使用设计抗原进行免疫接种导致了关键目标抗体突变的增强选择。由这些数据集构建的MSM对于指导这一设计方法至关重要，并揭示了表征蛋白质-蛋白质相互作用形成的难于观察的结构状态。