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

Rosetta Drug Design

Small molecule design consists of assembly, docking, and scoring. Since Rosetta already has a docking algorithm (RosettaLigand) and a scoring framework, all that is needed for small molecule design is an assembly algorithm. As an initial approach, we have chosen random assembly of fragments from an input library. The algorithm is represented in figure 1. Each cycle of design consists of extending the small molecule with random fragments chosen from a library, filtering small molecule designs based on energy score, and docking the new ligand using RosettaLigand.
In figure two we test our Rosetta assembly code. In the top panel acetylpepstatin was split into 6 fragments Five cycles of random assembly were used to generate the small molecules seen in the bottom panel.

Current Project Members: Rocco Moretti
Alumni Project Members: Gordon Lemmon , Dan Viox , Kristin Glab , Steven Combs

Meiler Lab © 2019

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