Project A07 – Innovative Rosetta algorithms for comparative modeling and docking of GPCRs
Project A07 focuses on the development of innovative computational technologies to support G protein-coupled receptor (GPCR) drug discovery. Specifically, we will (i) develop artificial intelligence technologies for the prediction of GPCR structure and dynamics with AlphaFold and RoseTTAFold, (ii) integrate limited electron paramagnetic resonance (EPR) / nuclear magnetic resonance (NMR) data with molecular modeling to detect biologically relevant states in an integrative structural biology setup, (iii) employ ultra-large library screening to identify novel agonist, antagonists, and allosteric modulators, and (iv) develop deep learning artificial intelligence structure- and ligand-based scoring functions for ultra-large library screening.
Project A07 focuses on the development of a Rosetta pipeline for comparative modeling and docking of GPCRs based on a combined conformational selection/induced fit paradigm. This novel approach uses RosettaCM to construct GPCR comparative models. It features fully flexible docking of partner proteins with simultaneous construction of loop regions (Aim I). Aim II modifies the RosettaLigand sampling algorithm to dock ensembles of small molecules simultaneously thereby enabling a new scoring function that ranks ligands according to their affinity or biological activity (Aim III). Aim IV benchmarks the overall pipeline.
Contact
Prof. Dr. Jens Meiler (Project Leader)
Leipzig University, Faculty of Medicine
Institute for Drug Development
Liebigstraße 19, D-04103 Leipzig
Phone +49 341 97 11801
E-Mail
Web meilerlab.org/
Web uniklinikum-leipzig.de/einrichtungen/wirkstoffentwicklung
Dr. Marjia Sorokina (PostDoc)
Leipzig University, Faculty of Medicine
Institute for Drug Development
Liebigstraße 19, D-04103 Leipzig
Resources
- RosettaCM
Publications
Melancon K, Pliushcheuskaya P, Meiler J, Künze G. Targeting ion channels with ultra-large library screening for hit discovery. Front Mol Neurosci. 2024 Jan 5;16:1336004.
Junker H, Meiler J, Schoeder CT. Interplay of thermodynamics and evolution within the ternary ligand-GPCR-G protein complex. Curr Opin Struct Biol. 2023 Jul 17;82:102656.
Ledwitch KV, Künze G, McKinney JR, Okwei E, Larochelle K, Pankewitz L, Ganguly S, Darling HL, Coin I, Meiler J. Sparse pseudocontact shift NMR data obtained from a non-canonical amino acid-linked lanthanide tag improves integral membrane protein structure prediction. J Biomol NMR. 2023 Apr 4.
Liessmann F, Künze G, Meiler J. Improving the Modeling of Extracellular Ligand Binding Pockets in RosettaGPCR for Conformational Selection. Int J Mol Sci. 2023; 24:7788.
Marlow B, Kuenze G, Meiler J, Koehler Leman J. Docking cholesterol to integ-ral membrane proteins with Rosetta. PLoS Comput Biol. 2023; 19:e1010947.
Okwei E, Smith ST, Bender BJ, Allison B, Ganguly S, Geanes A, Zhang X, Ledwitch K, Meiler J. Rosetta’s Predictive Ability for Low-Affinity Ligand Binding in Fragment-Based Drug Discovery. Biochemistry. 2023; 62:700-709.
Sala D, Batebi H, Ledwitch K, Hildebrand PW, Meiler J. Targeting in silico GPCR conformations with ultra-large library screening for hit discovery. Trends Pharmacol Sci. 2023; 44:150-61.
Sala D, Hildebrand PW, Meiler J. Biasing AlphaFold2 to predict GPCRs and Kinases with user-defined functional or structural properties. Front Mol Biosci. 2023; 10:1121962.
Schüß C, Vu O, Mishra NM, Tough IR, Du Y, Stichel J, Cox HM, Weaver CD, Meiler J, Emmitte KA, Beck-Sickinger AG. Structure-Activity Relationship Study of the High-Affinity Neuropeptide Y4 Receptor Positive Allosteric Modulator VU0506013. J Med Chem. 2023 Jul 13;66(13):8745-8766.
Brown BP, Vu O, Geanes AR, Kothiwale S, Butkiewicz M, Lowe EW Jr, Mueller R, Pape R, Mendenhall J, Meiler J. Introduction to the BioChemical Library (BCL): An Application-Based Open-Source Toolkit for Integrated Cheminformatics and Machine Learning in Computer-Aided Drug Discovery. Front Pharmacol. 2022 Feb 21;13:833099. doi: 10.3389/fphar.2022.833099. PMID: 35264967; PMCID: PMC8899505.
Del Alamo D, Sala D, McHaourab HS, Meiler J. Sampling alternative conformational states of transporters and receptors with AlphaFold2. Elife. 2022; 11.
Sala D, Del Alamo D, Mchaourab HS, Meiler J. Modeling of protein conformational changes with Rosetta guided by limited experimental data. Structure. 2022 May 12:S0969-2126(22)00140-X. doi: 10.1016/j.str.2022.04.013. Online ahead of print. PMID: 35597243.
Rudolf S, Kaempf K, Vu O, Meiler J, Beck-Sickinger AG, Coin I. Binding of Natural Peptide Ligands to the Neuropeptide Y5 Receptor. Angew Chem Int Ed Engl. 2022 Jan 26;61(5):e202108738. doi: 10.1002/anie.202108738 . PMID:34822209.
Zimmermann A, Vu O, Brüser A, Sliwoski G, Marnett LJ, Meiler J, Schöneberg T. Mapping the Binding Sites of UDP and Prostaglandin E2 Glyceryl Ester in the Nucleotide Receptor P2Y6. ChemMedChem. 2022, e202100683.
B Bertron JL, Duvernay MT, Mitchell SG, Smith ST, Maeng JG, Blobaum AL, Davis DC, Meiler J, Hamm HE, Lindsley CW. Discovery and Optimization of a Novel Series of Competitive and Central Nervous System-Penetrant Protease-Activated Receptor 4 (PAR4) Inhibitors. ACS Chem Neurosci. 2021; 12:4524-34.
Del Alamo D, Jagessar KL, Meiler J, Mchaourab HS. Methodology for rigorous modeling of protein conformational changes by Rosetta using DEER Distance Restraints. PLoS Comput Biol. 2021 Jun 16;17(6):e1009107. doi: 10.1371/journal.pcbi.1009107. Online ahead of print. PMID: 34133419.
Fischer TF, Schoeder CT, Zellmann T, Stichel J, Meiler J, Beck-Sickinger AG. Cyclic Analogues of the Chemerin C-Terminus Mimic a Loop Conformation Essential for Activating the Chemokine-like Receptor 1. Journal of medicinal chemistry. 2021;64(6):3048-58.
Gershkovich MM, Groß VE, Vu O, Schoeder CT, Meiler J, Prömel S, Kaiser A. Structural Perspective on Ancient Neuropeptide Y-like System reveals Hallmark Features for Peptide Recognition and Receptor Activation. J Mol Biol. 2021 Apr 16;433(13):166992. doi: 10.1016/j.jmb.2021.166992. Epub ahead of print. PMID: 33865871.
Li B, Mendenhall J, Capra JA, Meiler J. A Multitask Deep-Learning Method for Predicting Membrane Associations and Secondary Structures of Proteins. J Proteome Res. 2021 Jul 8. doi: 10.1021/acs.jproteome.1c00410. Epub ahead of print. PMID: 34236204.
Marlow B, Kuenze G, Li B, Sanders CR, Meiler J. Structural determinants of cholesterol recognition in helical integral membrane proteins. Biophysical journal. 2021;120(9):1592-604.
McKee AG, Kuntz CP, Ortega JT, Woods H, Most V, Roushar FJ, Meiler J, Jastrzebska B, Schlebach JP. Systematic profiling of temperature- and retinal-sensitive rhodopsin variants by deep mutational scanning. J Biol Chem. 2021; 297:101359.
Schuss C, Vu O, Schubert M, Du Y, Mishra NM, Tough IR, … Meiler J, Beck-Sickinger A. Highly Selective Y4 Receptor Antagonist Binds in an Allosteric Binding Pocket. Journal of medicinal chemistry. 2021;64(5):2801-14.
Vu O, Bender BJ, Pankewitz L, Huster D, Beck-Sickinger AG, Meiler J. The Structural Basis of Peptide Binding at Class A G Protein-Coupled Receptors. Molecules. 2021 Dec 30;27(1):210. doi:10.3390/molecules27010210. PMID: 35011444 Review.
Bender BJ, Marlow B, Meiler J. Improving homology modeling from low-sequence identity templates in Rosetta: A case study in GPCRs. PLoS computational biology. 2020;16(10): e1007597.
Kuenze G, Vanoye CG, Desai RR, Adusumilli S, Brewer KR, Woods H, McDonald EF, Sanders CR, George AL Jr, Meiler J. Allosteric mechanism for KCNE1 modulation of KCNQ1 potassium channel activation. Elife. 2020 Oct 23;9:e57680. doi: 10.7554/eLife.57680. PMID: 33095155; PMCID: PMC7584456.
Yang Z, Han S, Keller M, Kaiser A, Bender BJ, Bosse M, Burkert K, Kogler LM, Wifling D, Bernhardt G, Plank N, Littmann T, Schmidt P, Yi C, Li B, Ye S, Zhang R, Xu B, Larhammar D, Stevens RC, Huster D, Meiler J, Zhao Q, Beck-Sickinger AG, Buschauer A, Wu B. Structural basis of ligand binding modes at the neuropeptide Y Y1 receptor. Nature. 2018; 556:520-4.
Fu DY, Meiler J. RosettaLigandEnsemble: A Small-Molecule Ensemble-Driven Docking Approach. ACS Omega. 2018; 3:3655-64.
Fu DY, Meiler J. Predictive Power of Different Types of Experimental Restraints in Small Molecule Docking: A Review. J Chem Inf Model. 2018; 58:225-33.
Sliwoski G, Schubert M, Stichel J, Weaver D, Beck-Sickinger AG, Meiler J. Discovery of Small-Molecule Modulators of the Human Y4 Receptor. PLoS One. 2016; 11:e0157146.
Kaiser A, Muller P, Zellmann T, Scheidt HA, Thomas L, Bosse M, Meier R, Meiler J, Huster D, Beck-Sickinger AG, Schmidt P. Unwinding of the C-Terminal Residues of Neuropeptide Y is critical for Y(2) Receptor Binding and Activation. Angew Chem Int Ed Engl. 2015; 54:7446-9.
Wu H, Wang C, Gregory KJ, Han GW, Cho HP, Xia Y, Niswender CM, Katritch V, Meiler J, Cherezov V, Conn PJ, Stevens RC. Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator. Science. 2014; 344:58-64.
Pedragosa-Badia X, Sliwoski GR, Dong Nguyen E, Lindner D, Stichel J, Kaufmann KW, Meiler J, Beck-Sickinger AG. Pancreatic polypeptide is recognized by two hydrophobic domains of the human Y4 receptor binding pocket. J Biol Chem. 2014; 289:5846-59.
Conn PJ, Lindsley CW, Meiler J, Niswender CM. Opportunities and challenges in the discovery of allosteric modulators of GPCRs for treating CNS disorders. Nat Rev Drug Discov. 2014; 13:692-708.
Alexander NS, Preininger AM, Kaya AI, Stein RA, Hamm HE, Meiler J. Energetic analysis of the rhodopsin-G-protein complex links the alpha5 helix to GDP release. Nat Struct Mol Biol. 2014; 21:56-63.
Nguyen ED, Norn C, Frimurer TM, Meiler J. Assessment and challenges of ligand docking into comparative models of G-protein coupled receptors. PLoS One. 2013; 8:e67302
