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Deciphering the Coevolutionary Dynamics of L2 β-Lactamases via Deep Learning

Zhu, Yu; Gu, Jing; Zhao, Zhuoran; Chan, AW Edith; Mojica, Maria F; Hujer, Andrea M; Bonomo, Robert A; (2024) Deciphering the Coevolutionary Dynamics of L2 β-Lactamases via Deep Learning. Journal of Chemical Information and Modeling 10.1021/acs.jcim.4c00189. (In press). Green open access

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Abstract

L2 β-lactamases, serine-based class A β-lactamases expressed by Stenotrophomonas maltophilia, play a pivotal role in antimicrobial resistance (AMR). However, limited studies have been conducted on these important enzymes. To understand the coevolutionary dynamics of L2 β-lactamase, innovative computational methodologies, including adaptive sampling molecular dynamics simulations, and deep learning methods (convolutional variational autoencoders and BindSiteS-CNN) explored conformational changes and correlations within the L2 β-lactamase family together with other representative class A enzymes including SME-1 and KPC-2. This work also investigated the potential role of hydrophobic nodes and binding site residues in facilitating the functional mechanisms. The convergence of analytical approaches utilized in this effort yielded comprehensive insights into the dynamic behavior of the β-lactamases, specifically from an evolutionary standpoint. In addition, this analysis presents a promising approach for understanding how the class A β-lactamases evolve in response to environmental pressure and establishes a theoretical foundation for forthcoming endeavors in drug development aimed at combating AMR.

Type: Article
Title: Deciphering the Coevolutionary Dynamics of L2 β-Lactamases via Deep Learning
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1021/acs.jcim.4c00189
Publisher version: http://dx.doi.org/10.1021/acs.jcim.4c00189
Language: English
Additional information: © 2024 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY 4.0.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10191804
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