High-throughput structural modeling of the HIV transmission bottleneck

After three decades of research on human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS), a vaccine has yet to be discovered. Most theoretical and experimental work on HIV vaccines has focused on the relevant molecular interactions at systemic pH levels, but HIV is typically transmitted sexually at mucosal pH levels. We previously developed a computational approach for calculating pH-sensitivity which predicted optimal transmission at mucosal pH levels, and was validated by experimental electrophoretic measurements and envelope protein binding assays. We have recently augmented this approach using a unique combination of protein dynamical modeling, parallel computation, and data compression tools which enable high-throughput calculations. The resulting fully-automated pipeline was capable of predicting pH sensitivity for a recent study involving more than 250 unique HIV envelope proteins utilizing approximately 1 million individual electrostatic surface calculations. We provide strong evidence that supports the previous hypothesis of a computational approach to determining the pH sensitivity of HIV envelopes. Furthermore, a PCA-based indexing method is proposed that allows for a comparison of biomolecular structures in terms of electrostatic pH sensitivity. We utilize the results to predict highly transmissible HIV variants with implications for vaccine design and efficacy.