Life Sciences & Biotechnology
Title : | Computational Explorations of Membrane Spanning DNA Nanostructures for Cellular drug delivery |
Area of research : | Life Sciences & Biotechnology |
Principal Investigator : | Dr. Himanshu Joshi, Indian Institute Of Technology (IIT) Hyderabad, Telangana |
Timeline Start Year : | 2022 |
Timeline End Year : | 2024 |
Contact info : | hjoshi@bt.iith.ac.in |
Equipments : | Workstation
Nvidia Graphics Card |
Details
Executive Summary : | Despite rapid experimental advancement in the area of synthesizing membrane-spanning DNA nanopores, the mechanism of insertion is not well-understood. The goal of this project is to computationally explore the mechanism of the formation of DNA nanopores in biological membrane and assess their potential application for delivering the anticancer drugs such as doxorubicin. This project is based on a recent experimental finding which says that DNA nanopore can be used to flip lipid from one leaflet to the other leaflet. This synthetic DNA device named as DNA scramblase flips lipid 10,000 times faster than their biological counterparts. The simulations will determine how the lipid scrambling rate depends on lipid type and bilayer membrane composition, how the activity of the DNA scramblase alters from a healthy cell membrane to a cancerous cell’s membrane, and whether the lipid scrambling effect can be used to transport the drug molecule across the membrane. The outcome of our research work will help our experimental collaborators in rationally designing DNA nanopores for applications in cellular drug delivery. We believe that the curvature of the membrane captures the DNA and then the hydrophobic lipid anchors like cholesterol, ultimately pull the DNA into the membrane. To test this hypothesis, we will perform the simulations with a curved membrane which shows higher affinity to DNA. The analysis of the simulation trajectories is likely to solve the mystery of the formation of transmembrane DNA nanopores. The proposed research will also shed light on the specific molecular interactions which enable binding of DNA to the curved lipid bilayer membranes. These curved bilayers mimic the plasma membrane of a mammalian cell. Also, the thermal fluctuations lead to the ripples /deformation in the planner structure of the lipid bilayer membrane. To the best of our knowledge, the effect of the curvature to the DNA-lipid self-assembly is not studied so far. Elucidating the role of membrane curvature on lipid–DNA interactions will be critical in designing tools for DNA-assisted lipid fusion. The interaction between DNA and lipid is also important to our understanding of several biophysical processes such as viral infections, gene delivery, etc. Overall, the outcome of our simulations will enrich the fundamental understanding of forces that leads to self-assembled lipid-DNA nanostructures and pave the way to enable their future in-vivo as well as in-vitro applications. |
Total Budget (INR): | 26,20,800 |
Organizations involved