(334d) Molecular Simulations to Characterize the Assembly and Transport of Biomolecules in Solution and at Lipid Interfaces

A significant challenge in designing drug and gene delivery agents is understanding how their chemical structure and properties affect interfacial properties at the cell membrane and dictate their transport across the cell membrane. My research interest lies in developing multiscale simulations and computational techniques to understand the molecular mechanisms of how the structure of biomolecules affect: (1) their transport pathways across the cell membrane, and (2) their interaction with other biomolecules. In summary, my research focuses on utilizing the fundamentals of biophysics and chemical engineering along with computational tools to provide faster screening tools (e.g. screening of drugs for properties such as permeability across the lipid bilayer) and better designs for drug and gene delivery agents.

Research Experience

My research is focused on developing multiscale molecular dynamics (MD) simulations, state-of-the-art enhanced sampling techniques, and Python-coded analysis tools for two subareas.

(1) I study the translocation (or “flipping”) of charged peptide loops across the lipid bilayer that is valuable not only to design small cationic peptides for applications in gene/drug delivery but also to understand the large-scale conformational rearrangements that involve multiple charge translocation events in naturally occurring integral membrane proteins. I developed all-atom enhanced sampling simulations (i.e. Temperature Accelerated Molecular Dynamics) protocols to predict the likelihood of loop flipping without predefining a specific translocation pathway. Further, I run the string method with swarms of trajectories to find the minimum free energy path for translocation, which gives insights into engineering materials capable of bypassing the cell membrane.

(2) I study the amphiphilic behavior of bacterial signaling molecules that will allow us to understand their behavior in different biological environments that may help to control bacterial group behaviors such as virulence factor secretion, and biofilm formation. I predict the impact of their chemical structure on their aggregate morphology using alchemical free energy calculations using all-atom MD simulations. I then investigate their interactions with other amphiphilic biomolecules, such as lipids using coarse-grained MD simulations. I further collaborate with two experimental research groups at UW-Madison to gain better understanding of the process by validating simulation results with the experimental results and developing accurate prediction models.

My research experience has led me to work as an intern at Lawrence Livermore National Laboratory, where I systematically studied the effects of different parameters for calculating the free energy barrier of drug translocation across the lipid bilayer, which led to faster screening of drugs for permeability.