Journal Article

FZJ-2019-05276

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Exhaustive Search of Ligand Binding Pathways via Volume-Based Metadynamics

Capelli, R. (Corresponding author)FZJ* ; Carloni, P.FZJ* ; Parrinello, M.

2019
ACS Washington, DC

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Please use a persistent id in citations: http://hdl.handle.net/2128/23195  doi:10.1021/acs.jpclett.9b01183

Abstract: Determining the complete set of ligands’ binding–unbinding pathways is important for drug discovery and for rational interpretation of mutation data. Here we have developed a metadynamics-based technique that addresses this issue and allows estimating affinities in the presence of multiple escape pathways. Our approach is shown on a lysozyme T4 variant in complex with a benzene molecule. The calculated binding free energy is in agreement with experimental data. Remarkably, not only were we able to find all the previously identified ligand binding pathways, but also we identified three pathways previously not identified as such. These results were obtained at a small computational cost, making this approach valuable for practical applications, such as screening of small compound libraries.

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Contributing Institute(s):

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

Research Program(s):

1. 574 - Theory, modelling and simulation (POF3-574) (POF3-574)
2. HBP SGA2 - Human Brain Project Specific Grant Agreement 2 (785907) (785907)
3. HPC-aided design of drugs with improved kinetics of binding (jias5d_20181101) (jias5d_20181101)

Appears in the scientific report 2019

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

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