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.

Exhaustive Search of Ligand Binding Pathways via Volume-Based Metadynamics / R. Capelli, P. Carloni, M. Parrinello. - In: THE JOURNAL OF PHYSICAL CHEMISTRY LETTERS. - ISSN 1948-7185. - 10:12(2019), pp. 3495-3499. [10.1021/acs.jpclett.9b01183]

Exhaustive Search of Ligand Binding Pathways via Volume-Based Metadynamics

R. Capelli
Primo
;
2019

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.
Settore FIS/07 - Fisica Applicata(Beni Culturali, Ambientali, Biol.e Medicin)
Settore CHIM/02 - Chimica Fisica
Settore BIO/10 - Biochimica
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/933811
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