Allosteric communication in class A β-lactamases occurs via cooperative coupling of loop dynamics

  1. Ioannis Galdadas  Is a corresponding author
  2. Shen Qu
  3. Ana Sofia F Oliveira
  4. Edgar Olehnovics
  5. Andrew R Mack
  6. Maria F Mojica
  7. Pratul K Agarwal
  8. Catherine L Tooke
  9. Francesco Luigi Gervasio
  10. James Spencer
  11. Robert A Bonomo
  12. Adrian J Mulholland  Is a corresponding author
  13. Shozeb Haider  Is a corresponding author
  1. University College London, United Kingdom
  2. University of Bristol, United Kingdom
  3. Case Western Reserve University, United States
  4. Oklahoma State University, United States

Abstract

Understanding allostery in enzymes and tools to identify it, offer promising alternative strategies to inhibitor development. Through a combination of equilibrium and nonequilibrium molecular dynamics simulations, we identify allosteric effects and communication pathways in two prototypical class A β-lactamases, TEM-1 and KPC-2, which are important determinants of antibiotic resistance. The nonequilibrium simulations reveal pathways of communication operating over distances of 30 Å or more. Propagation of the signal occurs through cooperative coupling of loop dynamics. Notably, 50% or more of clinically relevant amino acid substitutions map onto the identified signal transduction pathways. This suggests that clinically important variation may affect, or be driven by, differences in allosteric behavior, providing a mechanism by which amino acid substitutions may affect the relationship between spectrum of activity, catalytic turnover and potential allosteric behavior in this clinically important enzyme family. Simulations of the type presented here will help in identifying and analyzing such differences.

Data availability

All analysis scripts have been uploaded on figshare with doi 10.6084/m9.figshare.13583384

Article and author information

Author details

  1. Ioannis Galdadas

    Chemistry ; Structural and Molecular Biology, University College London, London, United Kingdom
    For correspondence
    igaldadas@gmail.com
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2136-9723
  2. Shen Qu

    School of Pharmacy, University College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  3. Ana Sofia F Oliveira

    School of Chemistry, University of Bristol, Bristol, United Kingdom
    Competing interests
    No competing interests declared.
  4. Edgar Olehnovics

    School of Pharmacy, University College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  5. Andrew R Mack

    Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0131-7996
  6. Maria F Mojica

    Department of Infectious Diseases, Case Western Reserve University, Cleveland, United States
    Competing interests
    No competing interests declared.
  7. Pratul K Agarwal

    Department of Physiological Sciences and High-Performance Computing Center, Oklahoma State University, Stillwater, United States
    Competing interests
    Pratul K Agarwal, Pratul K Agarwal is the founder and owner of Arium BioLabs LLC..
  8. Catherine L Tooke

    School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
    Competing interests
    No competing interests declared.
  9. Francesco Luigi Gervasio

    Chemistry ; Structural and Molecular Biology, University College London, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4831-5039
  10. James Spencer

    School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
    Competing interests
    No competing interests declared.
  11. Robert A Bonomo

    Department of Infectious Diseases, Case Western Reserve University, Cleveland, United States
    Competing interests
    No competing interests declared.
  12. Adrian J Mulholland

    School of Chemistry, University of Bristol, Bristol, United Kingdom
    For correspondence
    adrian.mulholland@bristol.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1015-4567
  13. Shozeb Haider

    School of Pharmacy, University College London, London, United Kingdom
    For correspondence
    shozeb.haider@ucl.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2650-2925

Funding

AstraZeneca (Case Studentship)

  • Ioannis Galdadas

National Institute of Allergy and Infectious Diseases (R01AI072219)

  • Robert A Bonomo

National Institute of General Medical Sciences (GM105978)

  • Pratul K Agarwal

National Institutes of Health (RO1AI063517)

  • Robert A Bonomo
  • Shozeb Haider

Engineering and Physical Sciences Research Council (EP/M022609/1)

  • Ana Sofia F Oliveira
  • Adrian J Mulholland

Engineering and Physical Sciences Research Council (EP/N024117/1)

  • Ana Sofia F Oliveira
  • Adrian J Mulholland

Biotechnology and Biological Sciences Research Council (BB/L01386X/1)

  • Ana Sofia F Oliveira
  • Adrian J Mulholland

Medical Research Council (MR/T016035/1)

  • Catherine L Tooke
  • James Spencer
  • Adrian J Mulholland

National Institute of Allergy and Infectious Diseases (R01AI100560)

  • Robert A Bonomo

National Institute of Allergy and Infectious Diseases (R01AI063517)

  • Robert A Bonomo

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Yogesh K Gupta, University of Texas Health Science Center at San Antonio, United States

Publication history

  1. Received: January 14, 2021
  2. Accepted: March 19, 2021
  3. Accepted Manuscript published: March 23, 2021 (version 1)
  4. Accepted Manuscript updated: March 24, 2021 (version 2)
  5. Version of Record published: April 21, 2021 (version 3)

Copyright

© 2021, Galdadas et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ioannis Galdadas
  2. Shen Qu
  3. Ana Sofia F Oliveira
  4. Edgar Olehnovics
  5. Andrew R Mack
  6. Maria F Mojica
  7. Pratul K Agarwal
  8. Catherine L Tooke
  9. Francesco Luigi Gervasio
  10. James Spencer
  11. Robert A Bonomo
  12. Adrian J Mulholland
  13. Shozeb Haider
(2021)
Allosteric communication in class A β-lactamases occurs via cooperative coupling of loop dynamics
eLife 10:e66567.
https://doi.org/10.7554/eLife.66567

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    Supported by National Institutes of Health R01 HL122352 grant; ‘la Caixa’ Banking Foundation (HR18-00304); Fundación La Marató TV3: Ayudas a la investigación en enfermedades raras 2020 (LA MARATO-2020); Instituto de Salud Carlos III/FEDER/FSE; Horizon 2020 - Research and Innovation Framework Programme GA-965286 to JJ; the CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation), and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIN/AEI/10.13039/501100011033). American Heart Association postdoctoral fellowship 19POST34380706s to JVEN. Israel Science Foundation to OB and MA [824/19]. Rappaport grant [01012020RI]; and Niedersachsen Foundation [ZN3452] to OB; US-Israel Binational Science Foundation (BSF) to OB and TH [2019039]; Dr. Bernard Lublin Donation to OB; and The Duchenne Parent Project Netherlands (DPPNL 2029771) to OB. National Institutes of Health R01 AR068428 to DM and US-Israel Binational Science Foundation Grant [2013032] to DM and OB.