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Ligand binding free-energy calculations with funnel metadynamics.
Journal article

Ligand binding free-energy calculations with funnel metadynamics.

  • Raniolo S Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Institute of Computational Science, Lugano, Switzerland.
  • Limongelli V Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Institute of Computational Science, Lugano, Switzerland. vittoriolimongelli@gmail.com.
  • 2020-08-21
Published in:
  • Nature protocols. - 2020
Computer Graphics
Ligands
Models, Molecular
Molecular Targeted Therapy
Pharmaceutical Preparations
Protein Binding
Protein Conformation
Thermodynamics
Time Factors
User-Computer Interface
English The accurate resolution of the binding mechanism of a ligand to its molecular target is fundamental to develop a successful drug design campaign. Free-energy calculations, which provide the energy value of the ligand-protein binding complex, are essential for resolving the binding mode of the ligand. The accuracy of free-energy calculation methods is counteracted by their poor user-friendliness, which hampers their broad application. Here we present the Funnel-Metadynamics Advanced Protocol (FMAP), which is a flexible and user-friendly graphical user interface (GUI)-based protocol to perform funnel metadynamics, a binding free-energy method that employs a funnel-shape restraint potential to reveal the ligand binding mode and accurately calculate the absolute ligand-protein binding free energy. FMAP guides the user through all phases of the free-energy calculation process, from preparation of the input files, to production simulation, to analysis of the results. FMAP delivers the ligand binding mode and the absolute protein-ligand binding free energy as outputs. Alternative binding modes and the role of waters are also elucidated, providing a detailed description of the ligand binding mechanism. The entire protocol on the paradigmatic system benzamidine-trypsin, composed of ~105 k atoms, took ~2.8 d using the Cray XC50 piz Daint cluster at the Swiss National Supercomputing Centre.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/210245
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