BAGIM is an active community of Boston area scientists bringing together people from diverse fields of modeling and informatics to impact life and health sciences. BAGIM strives to create a forum for great scientific discussions covering a wide range of topics including data management, visualization, computational chemistry, drug discovery, protein structure, molecular modeling, structure-based drug design, data mining, software tools, and the sharing of goals and experiences. Our community is made up of participants from academia, government, and industry whose goal is to engage in the discussion of science involving a synthesis of theory and technology. Discussions sponsored by BAGIM are targeted to the needs and interests of informatics scientists, computational chemists, medicinal chemists, and statisticians. BAGIM also provides opportunities for networking within these disciplines as well as an arena for the dissemination of information of specific interest to the membership.

Wednesday, May 24, 2023

Julien Michel - Allostery under the lens of molecular dynamics simulations

 Please join us for joint BAGIM and SAGIM online event featuring speaker Julien Michel, EaStCHEM School of Chemistry, University of Edinburgh. Our groups would like to thank Cresset for sponsoring the event.

Date: April, 26th, 2023
Time: 10 am PT / 1 pm ET / 6 pm BT

Title: Allostery under the lens of molecular dynamics simulations

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.


Julien Michel is Professor of Biomolecular Simulation at the University of Edinburgh, and Director at the OpenBioSim Community Interest Company. He has over 20 years of experience in academic research in molecular simulation methodologies and their applications to simulations of biomolecules. He has a long-standing track record of collaborative research with the pharmaceutical industry and is a member of the academic consortia CCPBioSim and HECBioSim.

Background reading

‘’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

‘’Deconstructing Allostery: Computational Assessment of the Binding Determinants of Allosteric PTP1B Modulators’’ Hardie, A. ; Cossins, B. P. ; Lovera, S. ; Michel, J. ChemRxiv 2023 doi.org/10.26434/chemrxiv-2023-qwhz1

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