Protein Allostery using AI + simulation
Protein-protein interactions (PPI) involving kinase and scaffold proteins play a pivotal role in cellular signaling pathways, which are critical for regulating a myriad of cellular functions, including growth, differentiation, and apoptosis. The role of allostery, where the binding of a small molecule at one site on a protein affects the binding of another molecule at a different site, is crucial for the regulation of these protein-protein interactions. This regulatory mechanism allows for fine-tuned control over kinase activity and signal propagation. Dysregulation of these interactions can lead to aberrant signaling, contributing to the development and progression of diseases, including cancer, neurodegenerative disorders, and metabolic syndromes. My research aims to uncover hidden intricacies associated allostery mediated kinase PPI interactions by combining AlphaFold, machine learning and molecular simulation.
Role of water in ligand binding
Water is essential for life. In the absence of inhibitor , the binding site of biomolecules often remain solvated. Ligand binding resulted in release of tightly-bound/buried water molecules which increases the entropy and makes formation of protein ligand complex more favourable. However release of water molecules from active site is a slow process and often requires ultra long molecular dynamics simulations. Designing realistic reaction co-ordinates to capture water release upon drug binding thus play a critical role in understanding mechanism of drug binding and accurately predicting binding free energy. My research focuses on developing reaction co-ordinates which takes into account desolvation in context of protein-ligand binding. Read my article where we introduced a restraint potential that prevented the water molecules from getting trapped in the binding site of the host. The effect of the restraint potential was rigorously calculated by free-energy perturbation. Our method allowed us to accurately predict binding free energy for host-guest systems.
Kinetics of aromatic ring flipping
Aromatic ring flipping is a hallmark of protein dynamics and often get associated with allosteric modulation, cryptic pocket opening and breathing motion. In biophysics there has been a long history of using aromatic ring flipping as a probe to study protein dynamics. However such experiments are limited to small proteins. I want to predict kinetics and thermodynamics associated with aromatic ring flipping in bigger proteins which plays crucial role in allosteric modulation and opening of cryptic pocket. I plan to tackle the problem by performing ultra long MD simulations followed by Markov state modelling (MSM). MSM will allow us to predict kinetics and equilibrium population associated with ring flipping which can be validated by NMR experiments. Read my paper here where I discussed how aromatic ring flipping governs conformational dynamics of aspartic proteases.
Life in Computational Biology 