Journal Article

FZJ-2023-02854

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Drug Design in the Exascale Era: A Perspective from Massively Parallel QM/MM Simulations

Raghavan, B. (First author)FZJ* ; Paulikat, M. (First author)FZJ* ; Ahmad, K. ; Callea, L. ; Rizzi, A.FZJ* ; Ippoliti, E.FZJ* ; Mandelli, D. (Corresponding author)FZJ* ; Bonati, L. ; De Vivo, M. ; Carloni, P. (Corresponding author)FZJ*

2023
American Chemical Society Washington, DC

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Please use a persistent id in citations: doi:10.1021/acs.jcim.3c00557  doi:10.34734/FZJ-2023-02854

Abstract: The initial phases of drug discovery – in silico drug design – could benefit from first principle Quantum Mechanics/Molecular Mechanics (QM/MM) molecular dynamics (MD) simulations in explicit solvent, yet many applications are currently limited by the short time scales that this approach can cover. Developing scalable first principle QM/MM MD interfaces fully exploiting current exascale machines – so far an unmet and crucial goal – will help overcome this problem, opening the way to the study of the thermodynamics and kinetics of ligand binding to protein with first principle accuracy. Here, taking two relevant case studies involving the interactions of ligands with rather large enzymes, we showcase the use of our recently developed massively scalable Multiscale Modeling in Computational Chemistry (MiMiC) QM/MM framework (currently using DFT to describe the QM region) to investigate reactions and ligand binding in enzymes of pharmacological relevance. We also demonstrate for the first time strong scaling of MiMiC-QM/MM MD simulations with parallel efficiency of ∼70% up to >80,000 cores. Thus, among many others, the MiMiC interface represents a promising candidate toward exascale applications by combining machine learning with statistical mechanics based algorithms tailored for exascale supercomputers.

Note: Grant name: DBA01838 Innovative high-performance computing applied to neurodegenerative diseasesOpen access publication

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Contributing Institute(s):

1. Computational Biomedicine (IAS-5)
2. Computational Biomedicine (INM-9)

Research Program(s):

1. 5241 - Molecular Information Processing in Cellular Systems (POF4-524) (POF4-524)

Appears in the scientific report 2023

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Database coverage:
; ; ; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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