A Temperature Accelerated Sliced Sampling Study on Drug Binding/Unbinding <u>Shubhandra Tripathi</u> and Nisanth N. Nair <i>Department of Chemistry</i> <i>Indian Institute of Technology Kanpur</i> <i>208016, Kanpur, Uttar Pradesh, India</i>

Molecular dynamics simulations using enhanced sampling techniques are widely used to explore the rugged free energy landscapes of drug binding/unbinding in proteins. Collective variable based techniques for enhanced sampling have severe drawback that their free energy convergence is slow when the dimensionality of the landscape goes beyond two or three [1]. Sampling of large number of transverse coordinates are vital to obtain reliable free energy estimates and quick convergence. A controlled biased sampling is essential to overcome the “leak out” of biasing energies. Recently, we proposed a novel sampling technique called “Temperature Accelerated Sliced Sampling” (TASS) to overcome these limitations [1-2]. In this work, we applied the TASS method in modelling binding/unbinding reaction pathways of avibactam, a β-lactamase inhibitor, with Class C β-lactamase [3]. We obtain full atomistic details of the binding/unbinding reactions, the intermediate steps thereof, critical interactions and free energetics.
References
Awasthi, A., & Nair, N. N. WIREs Comp. Mol. Sci., 9(3) e1398 (2018)
Awasthi, S., et al. J. Chem. Phys. 146(9), 094-108 (2017)
Das, C. K., & Nair, N. N. Phys. Chem. Chem. Phys., 20(21), 14482-14490 (2018)