(192be) Reconstructing Ancient Sequences to Understand the Structure and Function Relationships of Modern Proteins

Zahra Shamsi, Alexander Moffett and Diwakar Shukla*, Department of Chemical and Biomolecular Engineering, UIUC

Abstract

Understanding protein structure and function relationship lies at the heart of modern drug discovery efforts ¹. Molecular dynamics simulation is one of the most powerful tools to study proteins dynamics and functions. The major challenge in protein simulation is efficient sampling of pathways associated with rare conformational transitions ². Advances in the field of genomics over the last decade, have led to uncovering the substantial gene sequencing information, which can be utilized as valuable unused information to enhance the simulation samplings.

Proteins are not just simple sequences of amino acids; they can adopt thousands of different three-dimensional conformations, which affect their function. Evolution changes a protein’s function by altering its conformational preferences. In this poster, we outline novel computational methods based on evolutionary information to guide the exploration of the long timescale behavior of the proteins ³. We employ these methods to investigate the activation and drug-selectivity mechanisms of human kinases that are implicated in numerous diseases including Cancer. A “new” methods combined with “old” enzymes, the ancestors dating back up to about billion years, provides an unexpected outlook for future intelligent design of drugs.

References:

[1] Agafonov, et al. Front. Mol. Biosci., 2, 1-8, 2015; [2] Shukla, et al. Nat. Commun., 5, 3397, 2014; [3] Shamsi, et al. Sci. Rep. InPress;