Life Sciences & Biotechnology
Title : | Deciphering the mechano-chemical insights into ATP binding induced conformation changes in ABCA1 contributing towards cholesterol efflux in the Reverse Cholesterol Pathway |
Area of research : | Life Sciences & Biotechnology |
Principal Investigator : | Dr. Arjun Ray, Indraprastha Institute Of Information Technology, Delhi |
Timeline Start Year : | 2023 |
Timeline End Year : | 2026 |
Contact info : | arjun@iiitd.ac.in |
Equipments : | GPU enabled workstation |
Details
Executive Summary : | ABCA1 plays an integral part in Reverse Cholesterol Transport (RCT) by fulfilling its role as the only known lipid transporter that is capable of facilitating unidirectional efflux of free cholesterol to poorly lipidated ApoA1. This interaction between ABCA1 and ApoA1 marks the rate limiting step in HDL genesis and is dependent on ABCA1 activity (that leads to lipid reorganization in the membrane). ABCA1 activity is dependent on its localization on the plasma membrane (in active conformation) as well as the physical state of the surrounding membrane. We know that the efflux of cholesterol is facilitated by ATP hydrolysis, but the conformation changes in the protein that help in recruitment and shuttling of cholesterol is not yet characterized. Cryo-EM snapshots of ATP bound and unbound ABCA1 protein were solved recently but to asses the exact changes in the protein structure, in-silico methods are needed. In this study, utilizing large-scale molecular dynamics simulations, we aim to study the effect of ATP hydrolysis on ABCA1 in its native membrane environment and functionally annotate the residues responsible for its activity. The project shall also involve developing novel computational tools for extensive and elaborate insights, e.g. Lipid- Force Distribution Analysis and Water-dynamics inside a cavity. These tools that shall be developed by advancing methods that already are established in our lab. Additionally, using IndiGen data, the mechano-chemical insights from the study will further help in characterizing biomarkers to detect susceptibility to atherosclerosis in Indian population. The totality of the project shall not only fill the missing gap of understanding for one of the most important lipid efflux protein's mechanism, it shall also be the foundation of novel drug targeting research as ABCA1 remains obscure as a target of regulation. |
Co-PI: | Dr. Murugan Arul Natarajan, Indraprastha Institute Of Information Technology, Delhi-110020 |
Total Budget (INR): | 21,98,190 |
Organizations involved