Biophysical Society Thematic Meeting | Hamburg 2022

Biophysics at the Dawn of Exascale Computers

Thursday Speaker Abstracts

PROTEIN DYNAMICS AND FUNCTION THROUGH THE LENS OF EVOLUTION Banu Ozkan 1 ; 1 Arizona State University, Physics, Tempe, AZ, USA Proteins are the most efficient nano-machines. Not only they perform a broad range of functions, but they exquisitely adapt and evolve. Thus, inferring evolutionary record of extant proteins offers a tractable and highly effective solution protein design. We have developed a physics-based metrics called the Dynamic Flexibility Index (DFI) to study protein evolution. DFI quantifies the resilience of a given position to the perturbations occurring at various parts of a protein using linear response theory, mimicking the multidimensional response when the protein’s conformational space is probed upon interaction with small molecules or other cellular constituents. In this talk we will discuss our structural dynamics analysis on TEM-1 enzymes. TEM-1 is a class A β - lactamase produced by gram negative bacteria as their defense against β - lactam antibiotics through hydrolysis of β -lactam ring. Modern TEM-1 have evolved from gram negative common ancestral, GNCA β -lactamase about 2 billion years ago. Resurrection studies of GNCA have revealed that evolution has preserved their 3-D fold, but surprisingly several remarkable changes have been observed in their biophysical properties. Ancestral GNCA exhibit promiscuity albeit mo derate efficiency, which enables it to provide resistance against several β - lactam antibiotics. This is in contrast with TEM- 1 β -lactamase which is more specific enzyme hydrolyzing only penicillin with a higher efficiency. Moreover, TEM-1 has functionally evolved by substituting about 50% of its residue positions while conserving not only the fold but also its catalytic sites residues. Are there minimum number substitutions that are required for modulating the evolution from promiscuity to substrate specificity? If so, what are their biophysical characteristics? Here we answer these questions by exploring conformation dynamics of ancestral and modern TEM-1 through a set of position specific dynamics metrics. Our analysis not only provides the mechanism of evolution of resistance but also allows us to predict the location of substitutions required to evolve from a promiscuous β -lactamase to degrade a specific antibiotic with a better efficiency.

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