The interplay of structure and dynamics: Insights from a survey of HIV-1 Reverse Transcriptase Crystal Structures

摘要

HIV-1 reverse transcriptase is a critical drug target for HIV treatment, and understanding the exact mechanisms of its function and inhibition would significantly accelerate the development of new anti-HIV drugs. It is well known that structure plays a critical role in protein function, but for reverse transcriptase, structural information has proven to be insufficient – despite enormous effort – to explain the mechanism of inhibition and drug resistance of non-nucleoside reverse transcriptase inhibitors. We hypothesize that the missing link is dynamics, information about the motions of the system. However, many of the techniques that give the best information about dynamics, such as solution NMR and molecular dynamics simulations, cannot be easily applied to a protein as large as reverse transcriptase. As an alternative, we combine elastic network modeling with simultaneous hierarchical clustering of structural and dynamic data. We present an extensive survey of the dynamics of reverse transcriptase bound to a variety of ligands and with a number of mutations, revealing a novel mechanism for drug resistance to non-nucleoside reverse transcriptase inhibitors. Hydrophobic core mutations restore active-state motion to multiple functionally significant regions of HIV-1 RT. This model arises out of a combination of structural and dynamic information, rather than exclusively from one or the other.