title: S4MPLE--Sampler for Multiple Protein-Ligand Entities: Methodology and Rigid-Site Docking Benchmarking.
abstract: This paper describes the development of the unified conformational sampling and docking tool called Sampler for Multiple Protein-Ligand Entities (S4MPLE). The main novelty in S4MPLE is the unified dealing with intra- and intermolecular degrees of freedom (DoF). While classically programs are either designed for folding or docking, S4MPLE transcends this artificial specialization. It supports folding, docking of a flexible ligand into a flexible site and simultaneous docking of several ligands. The trick behind it is the formal assimilation of inter-molecular to intra-molecular DoF associated to putative inter-molecular contact axes. This is implemented within the genetic operators powering a Lamarckian Genetic Algorithm (GA). Further novelty includes differentiable interaction fingerprints to control population diversity, and fitting a simple continuum solvent model and favorable contact bonus terms to the AMBER/GAFF force field. Novel applications-docking of fragment-like compounds, simultaneous docking of multiple ligands, including free crystallographic waters-were published elsewhere. This paper discusses: (a) methodology, (b) set-up of the force field energy functions and (c) their validation in classical redocking tests. More than 80% success in redocking was achieved (RMSD of top-ranked pose < 2.0 Å).
authors.affiliation: Laboratoire de Chemoinformatique; UMR 7141, Université de Strasbourg, 1 rue B. Pascal, Strasbourg 67000, France. hoffer.laurent@gmail.com.|Novalix, BioParc, bld Sébastien Brant, BP 30170, Illkirch 67405 Cedex, France. hoffer.laurent@gmail.com.
authors.forename: Laurent
authors.initials: L
authors.lastname: Hoffer
authors.affiliation: Department of Computer Science, Technical University, Cluj-Napoca 400027, Romania. camelia.chira@cs.utcluj.ro.
authors.forename: Camelia
authors.initials: C
authors.lastname: Chira
authors.affiliation: Laboratoire de Chemoinformatique; UMR 7141, Université de Strasbourg, 1 rue B. Pascal, Strasbourg 67000, France. g.marcou@unistra.fr.
authors.forename: Gilles
authors.initials: G
authors.lastname: Marcou
authors.affiliation: Laboratoire de Chemoinformatique; UMR 7141, Université de Strasbourg, 1 rue B. Pascal, Strasbourg 67000, France. varnek@unistra.fr.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Varnek
authors.affiliation: Laboratoire de Chemoinformatique; UMR 7141, Université de Strasbourg, 1 rue B. Pascal, Strasbourg 67000, France. dhorvath@unistra.fr.
authors.forename: Dragos
authors.initials: D
authors.lastname: Horvath
mesh_terms: D000465:Algorithms; D019985:Benchmarking; D003198:Computer Simulation; D008024:Ligands; D062105:Molecular Docking Simulation / Q000379:methods* / Q000592:standards; D011487:Protein Conformation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D012984:Software
chemical_list: D008024:Ligands; D011506:Proteins
keywords: conformational sampling; docking; force field fitting; genetic algorithms; interaction fingerprints