Viral Proteins and Cell Homeostasis, The Effect of Viroporins on Lipid Dynamics
HCV viroporin, p7, in a model membrane highlighting yellow cholesterol molecules in the bilayer core. The protein is colored in white, green, and blue for non-polar, polar, and charged amino acids, respectively.
Overview
Lipids are major components of cellular membranes, they are also used to store energy and in signaling cascades in the cell. Lipid droplets (LDs) are lipid bodies synthesized in the endoplasmic reticulum, and are involved in protein sorting and pathogen recognition.
Accumulation of LDs is extremely detrimental to the cell, but their mechanism and dynamics of formation are still not well characterized. Certain viral infections, such as hepatitis C virus (HCV), can interfere directly with both lipids and LD regulation. Patients infected with HCV have shown greater prevalence of steatosis, accumulation of fat in the liver, which can evolve into more serious conditions if untreated. HCV infects over 170 million people worldwide, and viral mutations result in drug resistance that requires development of new therapies and enhanced understanding of the virus mechanisms. Assembly of HCV occurs on the surface of LDs and viral particles have close resemblance to very-low-density-lipoproteins (VLDL) particles, which can make them “invisible” to the immune system. We use advanced simulation techniques to understand the interaction and energetics of p7, a key ion channel of HCV, with different lipid species. We are particularly interested in modeling its insertion mechanism and aggregation patterns on model membranes as it is a potential drug target to de-stabilize HCV infection by preventing the proper assembly of viral particles.
Another point of intertest on this system is to understand lipid-lipid interactions, and how these are enhanced or diminished due to HCV proteins. Viral assembly is known to remodel the local environment of membranes; p7 inserts and aggregates close to LD formation sites, where significant lipid sorting is already taking place. We are interested on the study of lipid clustering and their response/effect on p7 dynamics.
Viral assembly significantly remodels the local environment of host membranes. Students are currently using simulation techniques to model the interaction of p7, a key viroporin of HCV, with different lipid species. The dual role of p7 at different stages of the viral life cycle have identified it as a potential drug target, but its mechanism and impact on the lipid landscape and the dynamics of LDs are not fully understood. We are particularly interested in modeling the insertion mechanism and aggregation patterns of p7 on complex model membranes to further understand the intricate interactions with lipids during HCV infection and chronic effects.
