b7e5cd4b359f86189d2c6c28c3795169 ijmolsci_a2021v22n1p187.pdf 10470d313e55c9eea60e5745435d52f3f20fb666 ijmolsci_a2021v22n1p187.pdf b87f49dfcaf7b2bb2b269bb51a9ab3131ec1f92e6236982df1e129da35f1614d ijmolsci_a2021v22n1p187.pdf Title: Dynamical Correlations Reveal Allosteric Sites in G Protein-Coupled Receptors Subject: G protein-coupled Receptors (GPCRs) play a central role in many physiological processes and, consequently, constitute important drug targets. In particular, the search for allosteric drugs has recently drawn attention, since they could be more selective and lead to fewer side effects. Accordingly, computational tools have been used to estimate the druggability of allosteric sites in these receptors. In spite of many successful results, the problem is still challenging, particularly the prediction of hydrophobic sites in the interface between the protein and the membrane. In this work, we propose a complementary approach, based on dynamical correlations. Our basic hypothesis was that allosteric sites are strongly coupled to regions of the receptor that undergo important conformational changes upon activation. Therefore, using ensembles of experimental structures, normal mode analysis and molecular dynamics simulations we calculated correlations between internal fluctuations of different sites and a collective variable describing the activation state of the receptor. Then, we ranked the sites based on the strength of their coupling to the collective dynamics. In the 2 adrenergic (2AR), glucagon (GCGR) and M2 muscarinic receptors, this procedure allowed us to correctly identify known allosteric sites, suggesting it has predictive value. Our results indicate that this dynamics-based approach can be a complementary tool to the existing toolbox to characterize allosteric sites in GPCRs. Keywords: allosteric sites; GPCR; dynamical correlations; normal modes; coupled motions; molecular dynamics Author: Pedro Renault and Jesús Giraldo Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Sun Dec 27 09:27:56 2020 CET ModDate: Sun Dec 27 09:27:56 2020 CET Custom Metadata: yes Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 21 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 3005074 bytes Optimized: no PDF version: 1.5 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- EMNTUK+URWPalladioL-Ital Type 1 Custom yes yes no 159 0 TVNYMQ+URWPalladioL-Bold Type 1 Custom yes yes no 160 0 ENLEMO+VnURWPalladioL-Bold Type 1 Custom yes yes no 161 0 IBERJK+URWPalladioL-Roma Type 1 Custom yes yes no 162 0 TOZXSU+VnURWPalladioL Type 1 Custom yes yes no 165 0 ZHWQNQ+EURM10 Type 1 Builtin yes yes no 166 0 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いどびっふびびどはの〠 Item: Title: きちぴづひどちぬび〠ちのつ〠きづぴとはつび〠 Children: Item: Title: こぴひふっぴふひちぬ〠ぅのびづねぢぬづび〠 Children: Item: Title: ぅへばづひどねづのぴちぬ〠ぅのびづねぢぬづ〠はて〠ぴとづ〠〲ぁげ〠 Item: Title: ぅへばづひどねづのぴちぬ〠ぅのびづねぢぬづ〠はて〠ぴとづ〠き〲〠きふびっちひどのどっ〠げづっづばぴはひ〠 Item: Title: ぎはひねちぬ〠きはつづ〠ぁのちぬべびどび〠 Item: Title: きはぬづっふぬちひ〠いべのちねどっび〠こどねふぬちぴどはのび〠 Item: Title: ごとづ〠ぃはぬぬづっぴどぶづ〠ざちひどちぢぬづ〠〠 Item: Title: ぃちぬっふぬちぴどはの〠はて〠ぉのぴづひ〭げづびどつふづ〠いどびぴちのっづび〠 Item: Title: ぃはふばぬどので〠ぢづぴぷづづの〠ぉのぴづひ〭げづびどつふづ〠いどびぴちのっづび〠ちのつ〠〠 Item: Title: いづぴづひねどのちぴどはの〠はて〠げづっづばぴはひび〧〠こどぴづび〠 Item: Title: ぃはふばぬどので〠ぢづぴぷづづの〠こどぴづび〠ちのつ〠〠 Item: Title: げづてづひづのっづび Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: TVNYMQ+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 121 FontDescriptor: FontName: TVNYMQ+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: ENLEMO+VnURWPalladioL-Bold FontSubset: true FirstChar: 243 LastChar: 243 FontDescriptor: FontName: ENLEMO+VnURWPalladioL-Bold Flags: 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