Project A07 – Innovative Rosetta algorithms for comparative modeling and docking of GPCRs  

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.


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


(Collection of resources used and or created by the project)


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.

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 JBeck-Sickinger AGCoin 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 JSchöneberg T. Mapping the Binding Sites of UDP and Prostaglandin E2 Glyceryl Ester in the Nucleotide Receptor P2Y6. ChemMedChem. 2022, e202100683.

Del Alamo D, Jagessar KL, Meiler J, Mchaourab HSMethodology 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.

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.

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.

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