ff99d89e0711febe2657f7caa6f4c999 intjoumolsci_a2019v20p3155.pdf 4202864be4c3abfb5d0399ee367711b4e899e3ae intjoumolsci_a2019v20p3155.pdf dd9571fc32400503b5277390e9f677d18a1b6fe2327481be869c1f447a95221e intjoumolsci_a2019v20p3155.pdf Title: GPathFinder: Identification of Ligand-Binding Pathways by a Multi-Objective Genetic Algorithm Subject: Protein–ligand docking is a widely used method to generate solutions for the binding of a small molecule with its target in a short amount of time. However, these methods provide identification of physically sound protein–ligand complexes without a complete view of the binding process dynamics, which has been recognized to be a major discriminant in binding affinity and ligand selectivity. In this paper, a novel piece of open-source software to approach this problem is presented, called GPathFinder. It is built as an extension of the modular GaudiMM platform and is able to simulate ligand diffusion pathways at atomistic level. The method has been benchmarked on a set of 20 systems whose ligand-binding routes were studied by other computational tools or suggested from experimental “snapshots”. In all of this set, GPathFinder identifies those channels that were already reported in the literature. Interestingly, the low-energy pathways in some cases indicate novel possible binding routes. To show the usefulness of GPathFinder, the analysis of three case systems is reported. We believe that GPathFinder is a software solution with a good balance between accuracy and computational cost, and represents a step forward in extending protein–ligand docking capacities, with implications in several fields such as drug or enzyme design. Keywords: multi-objective genetic algorithm; molecular modeling; ligand diffusion; computational chemistry; molecular docking; drug design Author: José-Emilio Sánchez-Aparicio, Giuseppe Sciortino, Daniel Viladrich Herrmannsdoerfer, Pablo Orenes Chueca, Jaime Rodríguez-Guerra Pedregal and Jean-Didier Maréchal Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.18 CreationDate: Fri Jun 28 08:10:27 2019 CEST ModDate: Fri Jun 28 08:10:27 2019 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 18 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 4048683 bytes Optimized: no PDF version: 1.5 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- ENIJES+URWPalladioL-Ital Type 1 Custom yes yes no 95 0 TIXQBR+URWPalladioL-Bold Type 1 Custom yes yes no 96 0 IOJCNK+VnURWPalladioL-Bold Type 1 Custom yes yes no 97 0 XABJQI+URWPalladioL-Roma Type 1 Custom yes 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ごひちのびばはひぴぜ〴ぜ〰はてぜ〴ぜ〰ぇぬべっづひはぬぜ〴ぜ〰ぁっひはびびぜ〴ぜ〰ぁぱふちばはひどのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㈩‾㸊⡜㌷㙜㌷㝜〰さのぢどのつどのでぜ〴ぜ〰はてぜ〴ぜ〰ちぜ〴ぜ〰こふどっどつづぜ〴ぜ〰ぉのとどぢどぴはひぜ〴ぜ〰てひはねぜ〴ぜ〰とぉいく〱ぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰えふねちのぜ〴ぜ〰ぃべぴはっとひはねづぜ〴ぜ〰ぐ〴〵〰ぜ〴ぜ〰〲ぃ〱〹ぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: さのぢどのつどのでぜ〴ぜ〰はてぜ〴ぜ〰ちぜ〴ぜ〰こふどっどつづぜ〴ぜ〰ぉのとどぢどぴはひぜ〴ぜ〰てひはねぜ〴ぜ〰とぉいく〱ぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰えふねちのぜ〴ぜ〰ぃべぴはっとひはねづぜ〴ぜ〰ぐ〴〵〰ぜ〴ぜ〰〲ぃ〱〹ぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: えふねちのぜ〴ぜ〰ぃべぴはっとひはねづぜ〴ぜ〰ぐ〴〵〰ぜ〴ぜ〰〲ぃ〱〹ぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: きちぴづひどちぬびぜ〴ぜ〰ちのつぜ〴ぜ〰きづぴとはつびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮ㄩ‾㸊⡜㌷㙜㌷㝜〰ぐちぴとぷちべぜ〴ぜ〰ぇづのづひちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㈩‾㸊⡜㌷㙜㌷㝜〰ぐちぴとぷちべぜ〴ぜ〰ぅぶちぬふちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰ぐちぴとぷちべぜ〴ぜ〰げづてどのづねづのぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㐩‾㸊⡜㌷㙜㌷㝜〰こづぴぜ〴ぜ〰ふばぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ぇぁぜ〴ぜ〰ぐちひちねづぴづひびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㔩‾㸊⡜㌷㙜㌷㝜〰あづのっとねちひにぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㘩‾㸊⡜㌷㙜㌷㝜〰さびちぢどぬどぴべ〬ぜ〴ぜ〰ぁぶちどぬちぢどぬどぴべ〬ぜ〴ぜ〰ちのつぜ〴ぜ〰ぃはねばふぴちぴどはのちぬぜ〴ぜ〰ぃはびぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Children: Item: Title: ぐちぴとぷちべぜ〴ぜ〰ぇづのづひちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㈩‾㸊⡜㌷㙜㌷㝜〰ぐちぴとぷちべぜ〴ぜ〰ぅぶちぬふちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰ぐちぴとぷちべぜ〴ぜ〰げづてどのづねづのぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㐩‾㸊⡜㌷㙜㌷㝜〰こづぴぜ〴ぜ〰ふばぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ぇぁぜ〴ぜ〰ぐちひちねづぴづひびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㔩‾㸊⡜㌷㙜㌷㝜〰あづのっとねちひにぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㘩‾㸊⡜㌷㙜㌷㝜〰さびちぢどぬどぴべ〬ぜ〴ぜ〰ぁぶちどぬちぢどぬどぴべ〬ぜ〴ぜ〰ちのつぜ〴ぜ〰ぃはねばふぴちぴどはのちぬぜ〴ぜ〰ぃはびぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: ぐちぴとぷちべぜ〴ぜ〰ぅぶちぬふちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰ぐちぴとぷちべぜ〴ぜ〰げづてどのづねづのぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㐩‾㸊⡜㌷㙜㌷㝜〰こづぴぜ〴ぜ〰ふばぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ぇぁぜ〴ぜ〰ぐちひちねづぴづひびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㔩‾㸊⡜㌷㙜㌷㝜〰あづのっとねちひにぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㘩‾㸊⡜㌷㙜㌷㝜〰さびちぢどぬどぴべ〬ぜ〴ぜ〰ぁぶちどぬちぢどぬどぴべ〬ぜ〴ぜ〰ちのつぜ〴ぜ〰ぃはねばふぴちぴどはのちぬぜ〴ぜ〰ぃはびぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: ぐちぴとぷちべぜ〴ぜ〰げづてどのづねづのぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㐩‾㸊⡜㌷㙜㌷㝜〰こづぴぜ〴ぜ〰ふばぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ぇぁぜ〴ぜ〰ぐちひちねづぴづひびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㔩‾㸊⡜㌷㙜㌷㝜〰あづのっとねちひにぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㘩‾㸊⡜㌷㙜㌷㝜〰さびちぢどぬどぴべ〬ぜ〴ぜ〰ぁぶちどぬちぢどぬどぴべ〬ぜ〴ぜ〰ちのつぜ〴ぜ〰ぃはねばふぴちぴどはのちぬぜ〴ぜ〰ぃはびぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: こづぴぜ〴ぜ〰ふばぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ぇぁぜ〴ぜ〰ぐちひちねづぴづひびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㔩‾㸊⡜㌷㙜㌷㝜〰あづのっとねちひにぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㘩‾㸊⡜㌷㙜㌷㝜〰さびちぢどぬどぴべ〬ぜ〴ぜ〰ぁぶちどぬちぢどぬどぴべ〬ぜ〴ぜ〰ちのつぜ〴ぜ〰ぃはねばふぴちぴどはのちぬぜ〴ぜ〰ぃはびぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: あづのっとねちひにぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㘩‾㸊⡜㌷㙜㌷㝜〰さびちぢどぬどぴべ〬ぜ〴ぜ〰ぁぶちどぬちぢどぬどぴべ〬ぜ〴ぜ〰ちのつぜ〴ぜ〰ぃはねばふぴちぴどはのちぬぜ〴ぜ〰ぃはびぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: さびちぢどぬどぴべ〬ぜ〴ぜ〰ぁぶちどぬちぢどぬどぴべ〬ぜ〴ぜ〰ちのつぜ〴ぜ〰ぃはねばふぴちぴどはのちぬぜ〴ぜ〰ぃはびぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: ぃはのっぬふびどはのびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: げづてづひづのっづび Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: TIXQBR+URWPalladioL-Bold FontSubset: true FirstChar: 2 LastChar: 122 FontDescriptor: FontName: TIXQBR+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: IOJCNK+VnURWPalladioL-Bold FontSubset: true FirstChar: 161 LastChar: 189 FontDescriptor: FontName: IOJCNK+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: 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