HIV research experiments
Rapid Conformational Fluctuations of Disordered HIV-1 Fusion Peptide in Solution.
The conformationally flexible fusion peptide (FP) of HIV-1 is indispensible for viral infection of host cells, due to its ability to insert into and tightly couple with phospholipid membranes. There are conflicting reports on the membrane-associated structure of FP, and solution structure information is limited, yet such a structure is the target for a novel class of antiretroviral inhibitors. An ensemble of explicit solvent molecular dynamics simulations, initiated from a disordered HIV-1 FP (aggregate time of ∼30 μs), revealed that while the vast majority of conformations predominantly lack secondary structure, both spontaneous formation and rapid interconversion of local secondary structure elements occur, highlighting the structural plasticity of the peptide. Therefore, even at this rapid time scale, FP constitutes a diverse and flexible conformational ensemble in solution. Secondary structure clustering reveals that the most prominent ordered elements are α- and 3-10-helical subsets of membrane-bound conformations, while trace populations within 2 Å RMSD of all complete membrane-bound conformations are found to pre-exist in the solution ensemble. Since inhibitor bound conformations of FP are only rarely found, FP inhibitors could function by modulating the conformational ensemble and binding to nonfusogenic FP structures. A thermodynamic characterization of the most prominent ordered nonfusogenic structures could facilitate the future design of improved FP inhibitors.
- Venken T, Voet A, De Maeyer M, De Fabritiis G, Sadiq SK, Rapid Conformational Fluctuations of Disordered HIV-1 Fusion Peptide in Solution. Journal of chemical theory and computation 2013. doi:10.1021/ct300856r
Simulating the maturation of HIV protease
WU tags: HIVPR
One of the most intriguing aspects of the whole HIV maturation process is how the "scissors" protein, the protease, first emerges. There is a chicken-and-egg type paradox to understand here because every mature protease molecule comes from an immature form, being chained up within the long polyprotein "ropes" that it cuts. So if the "scissors" are initially in the "rope", how do the first "scissors" get free? Answering this question within an atomic level of accuracy requires performing molecular dynamics simulations at the current limit of computational power. GPUGRID technology allows us to successfully tackle this problem and we have been able to show that the first "scissors" can cut itself free from the "rope" within which it is chained. Fascinatingly, it does this by binding one of its own ends, initially connected to another protein in the "rope", to its own active site which in turn performs the cutting. This event is at the root of the whole maturation process and if HIV protease can be stopped while it is still becoming mature, then the virus particle as a whole cannot become mature. Accessing the nascent structures of HIV protease provides a novel and critical target for the development of ARVs in the fight against HIV/AIDS.
- S. K. Sadiq, F. Noé, and G. De Fabritiis, Kinetic characterization of the critical step in HIV-1 protease maturation, PNAS Published online November 26, 2012
Molecular simulations of the HIV protease flexibility
WU tags: HIVPR
Viral particles (virions) of HIV become mature and infectious through the action of the viral enzyme known as HIV protease, which acts like a pair of "scissors", cutting long polyprotein chains into shape that then go on to form the structure of a new virion. The structure, dynamics and function of this highly flexible protein have been extensively studied and have led to many antiretroviral inhibitors (ARVs) that today treat HIV in a limited way. However, the complete process by which the protease changes shape to perform its function are still not well understood at the atomic level, because such changes occur on computationally intractable timescales. Understanding the conformational changes that occur in the protease are of central importance in the design of a new class of structure-based ARVs that can target the protease in its alternate conformations. GPUGRID technology allows us to access these alternate conformations providing a basis for enhanced medical treatment of HIV/AIDS.
- S. K. Sadiq and G. De Fabritiis, Explicit solvent dynamics and energetics of HIV-1 protease flap-opening and closing, Proteins 78, 2873 (2010)