Allostery under the lens of molecular dynamics simulations

Aug 09, 2023

Posted by Cresset

On Wednesday 26th April 2023, we sponsored a virtual session hosted by the Boston Area Group for Informatics and Modeling (BAGIM) and their equivalent group in San Diego, SAGIM.

Professor Julien Michel, Professor of Biomolecular Simulation at The University of Edinburgh and member of Cresset’s SAB, presented ‘Allostery under the lens of molecular dynamics simulations’. He discussed molecular dynamics (MD) simulation methodologies developed to interrogate protein conformational ensembles and provide insight into protein allostery.

Thank you very much to Julien for his efforts in preparing for and presenting at the session, and to all those who were able to attend and make the event a success. If you weren’t able to attend, and the topic is of interest to you, we’d very much recommend that you catch up, via the recording further down the page.

Session abstract

Allosteric regulation of protein function can be interpreted as perturbations of conformational energy landscapes induced by protein structure modification. While the framework is generally accepted, it is currently challenging to construct models of protein conformational ensembles with sufficient spatiotemporal resolution and accuracy to inform drug discovery projects.

This presentation will discuss molecular dynamics (MD) simulation methodologies developed to interrogate protein conformational ensembles and provide insights into protein allostery.

Cyclophilin enzymes have been proposed as model systems to study links between protein dynamics and enzymatic function. We have used MD simulations with umbrella sampling (US) calculations and Markov State Models (MSM) to demonstrate that sub-microsecond timescale conformational motions in Cyclophilin A are sufficient to explain the functional effect of single point mutations outside of the enzyme’s active site.

The phosphatase PTP1B is a classic example of an enzyme that can be allosterically inhibited with small molecules, potentially offering opportunities to overcome drug development difficulties associated with targeting of the active site. We have combined steered MD (sMD) and equilibrium MD simulations to generate MSMs of the enzyme’s WPD loop dynamics in complex with different small molecules, including experimentally validated allosteric inhibitors, and fragments obtained by deconstruction of these inhibitors. Comparative analysis of the resulting conformational ensembles enables classification of binders according to their allosteric potential and provides insights into specific protein conformational states and ligand binding modes that correlate with allosteric inhibition. Altogether these findings highlight the potential for rational design of allosteric modulators in drug discovery campaigns.

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Session recording



About the Boston Area Group for Informatics and Modeling

The Boston Area Group for Informatics and Modeling (BAGIM) is an active group of Boston area scientists bringing together people from the diverse fields of modeling and informatics to impact health and life sciences. BAGIM strives to create a forum for great scientific discussions, covering a wide range of topics, highly relevant to the work that Cresset does, including computational chemistry, drug discovery, protein structure, molecular modeling, structure-based drug design, and software tools.

Background reading

  1. Allosteric effects in cyclophilin mutants may be explained by changes in nano-microsecond time scale motions. Wapeesittipan, P. ; Mey, A. S. J. S. ; Walkinshaw, M. D. ; Michel, J. Commun. Chem. 2: 41, 2019 doi:10.1038/s42004-019-0136-1
  2. Deconstructing Allostery: Computational Assessment of the Binding Determinants of Allosteric PTP1B Modulators. Hardie, A. ; Cossins, B. P. ; Lovera, S. ; Michel, J. ChemRxiv 2023

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