Enzymes are remarkable molecular systems with the ability to catalyze biochemical reactions efficiently, with high specificity and under mild, physiological conditions. Computational modeling and simulation can provide atomic-level understanding of the dynamics and reactions of these biomolecules. Irrespective of the complexity encountered in enzymes and the short lifetime of their transition state structures, these can be directly probed by simulations to study the biochemical reaction intermediates and the transition state structures. Currently, the large size of these enzymes restricts the application of quantum mechanical methods to investigate the entire enzyme. A quantum mechanical (QM) description is required for regions involving electronic rearrangement such as the breaking and formation of bonds. However, in biomolecular systems, the electrostatic effects exerted by the environment play a vital role and cannot be neglected. Hence, coupling the quantum mechanical description for the active region and molecular mechanical description for the environment via quantum mechanics/molecular mechanics (QM/MM) methods becomes essential for the biomolecular reactions.
I am employing simulations to probe the following-
1. Cooperativity: Some enzymes have multiple binding sites, and the binding to the sites can be enhanced/decreased on binding at another site. Such an enzyme may include several subunits working in cooperation with each other. The interactions at the catalytic and oligomeric interface are vital for the opening and closing of such enzymes, facilitating the reactions and the release of products.
2. Allosteric Regulation: This refers to the ability of a molecule to affect an enzyme's activity without binding to the active site.
3. Role Of Metal Ions: Many enzymes require a metal ion as a co-factor to catalyze the reaction. The number of metal ions actually required for catalysis as well as the information regarding the possible different mechanisms depending on the number of metal ions further aid in answering “How do enzymes work”?
4. Mutation and Enzyme Function: Deciphering the functional role of specific enzymatic residues, which when mutated, inhibit the activity of the enzyme. Enzyme disorders can lead to deadly diseases such as cancer. Knowing the detailed mechanism, including the structural and functional role of active site residues in the reactant, product as well as the transition states provides us a tool to tweak the enzyme’s activity. We can reveal novel pathways for the treatment of these diseases and facilitate designing new drugs.
5. Improvement and application of Density Functional based Tight Binding (DFT-B) methods for investigation of biomolecules.