Atomic-level characterization of the human immunodeficiency virus type 1 envelope glycoproteins using molecular dynamic simulations.

Abstract

The human immunodeficiency virus attacks the body's immune system and if left untreated can progress into acquired immunodeficiency syndrome (AIDS) which leads to the inability to fight infection. The most common form of the virus, Human immunodeficiency virus type 1 (HIV-1), enters host cells after the envelope (Env) glycoprotein trimer [(gp120/41)3] which is a class I fusion protein binds the CD4 receptor and a coreceptor, either CCR5 or CXCR4. Binding to the CD4 receptor induces conformational changes that allow mature (cleaved) Env to transition from a closed pretriggered state (state-1) to open states that are needed for the fusion process (state-2 and state-3). However, the closed conformational state of the Env trimer is not yet known. This study aims to characterize local and global conformational changes of the closed and open states of the Env trimer and to determine the dynamic behavior of the glycoprotein trimer through a combination of equilibrium and nonequilibrium molecular dynamic (MD) simulations. The MD simulations were done using previously determined structures in the state-2 form of the uncleaved glycoprotein trimer, precursors to the mature trimer, that are able occupy all three states of the mature Env, previously characterized through electron microscopy (EM). Nonequilibrium MD simulations allowed us to determine the transition pathway between open and closed states and using microsecond-level equilibrium MD simulations we were able to characterize the differential dynamic behavior of closed and open states.