Meiler Lab

Computational Chemical and Structural Biology

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Protein de-novo Folding

Methods Development
Contact Prediction BCL Align Sequence Alignment and Fold Recognition Sparse EPR Data guided Protein Structure Elucidation Jufo9D Secondary Structure and TM Span Prediction Protein Structure Prediction using Fold Templates BCL::Cluster: Clustering biological molecules with PyMOL visualization Gradient Minimization for Structure Refinement RosettaTMH
Applications
Modeling of Protein IIIA Structure Determination of DsbB using Paramagnetic Restraints Structure determination of KCNE3 using paramagnetic restraints

Protein Structure Prediction from Sparse Data

Methods Development
Protein Structure Prediction Cryo-EM Fit Cryo-EM Guided Protein Fold Elucidation Membrane Protein Structure Prediction using Sparse NMR Restraints RosettaEPR BCL::EMFitMinimize Protein Structure Prediction using SAXS Data
Applications
Modeling Rhodopsin Interaction with G-Protein and Arrestin Mechanism of Activation of the heterotrimeric G protein alpha subunit

Cheminformatics

Methods Development
Chemical Shift Prediction PharmMap Method Development for QSAR Ligand-based Virtual Screening Development of RosettaQSAR Knowledge-Based Small Molecule Conformational Sampling Novel HTS Datasets composed to benchmark ligand-based QSAR Modeling
Applications
mGluR5 Related Neurological Diseases Allosteric Modulators of Neuropeptide Y Receptors Malaria - Inhibition of beta-Hematin Crystallization in Plasmodium falciparum Rapid in silico target identification for anti-malarials

Protein-Protein Interactions

Applications
Structural Characterization of HoxA11 HIV Antibody/Antigens Interactions Antibiotics- Protein/Peptide Interfaces Antibody/Antigens Interaction

Methods Development
Rosetta Drug Design Rosetta Design Modeling Partial Covalent Interactions in Protein Ligand Interfaces RosettaLigandEnsemble Drug Design through Foldit Video Game
Applications
Structural Determinants of Antidepressant Drugs GPCR Model Building, Refinement, and Ligand Docking HIV-1 Protease Inhibitor Docking Protein-Ligand Interaction as Cancer Therapeutics

Applications
Evolution of TIM Barrels Chemical Basis of Ligand-Macromolecule Recognition

Structural Characterization of HoxA11

HoxA11 is a transcription factor that plays a critical role in embryonic development and is required for female fertility. Like all Hox proteins, HoxA11 contains a highly conserved homeodomain that binds DNA. However, the rest of the protein shows low levels of secondary structure, large stretches of disordered regions, and no easily detectable similarity to any fold in the PDB. De novo structure prediction using ROSETTA reveals a region outside of the homeodomain that folds independently into a small helical bundle similar to those seen in different DNA binding domains. We are pursuing structural characterization of HoxA11 to test this hypothesis and to elucidate the molecular basis of Hox-dependent transcriptional activation mechanisms. Since this region of the protein also contains sites that are believed to be important in the evolution of pregnancy in mammals, our results may provide insight into how novel developmental pathways evolve.

Comparative model of the HoxA11 homeodomain based on the crystal structure of HoxA9 (1pufA)

Alumni Project Members: Laura Mizoue , Caitlin Heuberger , Joel Harp , Soumya Ganguly , Heather Darling

Meiler Lab © 2019

Center for Structural Biology
465 21st Ave South, BIOSCI/MRBIII
Vanderbilt University, Nashville, TN