A5044975181- Cardiomyopathy and Myosin Studies
- Protein Structure and Dynamics
- RNA and protein synthesis mechanisms
- Computational Drug Discovery Methods
- Mass Spectrometry Techniques and Applications
- Enzyme Structure and Function
- RNA Research and Splicing
- Advanced Proteomics Techniques and Applications
- Advanced Electron Microscopy Techniques and Applications
- Signaling Pathways in Disease
- Metabolomics and Mass Spectrometry Studies
- Cancer therapeutics and mechanisms
- Force Microscopy Techniques and Applications
- Genetics, Bioinformatics, and Biomedical Research
- Machine Learning in Materials Science
- Cardiovascular Effects of Exercise
- Chemical Synthesis and Analysis
- Ion-surface interactions and analysis
- Viral Infections and Immunology Research
- Monoclonal and Polyclonal Antibodies Research
- Virus-based gene therapy research
- Electron and X-Ray Spectroscopy Techniques
- Biochemical and Molecular Research
- Receptor Mechanisms and Signaling
- Cell Adhesion Molecules Research
The Ohio State University
2016-2025
Florida State University
2021
University of California, San Diego
2012-2015
Center for Theoretical Biological Physics
2012-2015
Howard Hughes Medical Institute
2012-2015
U.S. National Science Foundation
2012-2014
Foundation Center
2014
Linde (United States)
2013
Vanderbilt University Medical Center
2007-2012
Vanderbilt University
2009-2012
Significance Uncoupling agents might be expected to generally cytotoxic, but many US Food and Drug Administration (FDA)-approved drugs do have activity as uncouplers, in addition targeting enzymes. There is therefore interest the discovery of antibiotics that such multitarget activity. Here, we show some FDA-approved drugs, clofazimine, clomiphene, bedaquiline, with antiinfective act uncouplers. Using molecular dynamics-based silico screening, also discovered brain cancer drug lead vacquinol...
Defensins are effectors of the innate immune response with potent antibacterial activity. Their role in antiviral immunity, particularly for non-enveloped viruses, is poorly understood. We recently found that human alpha-defensins inhibit adenovirus (HAdV) by preventing virus uncoating and release endosomalytic protein VI during cell entry. Consequently, AdV remains trapped endosomal/lysosomal pathway rather than trafficking to nucleus. To gain insight into mechanism defensin-mediated...
Significance There is a large gap between the number of protein complex structures currently solved and functionally relevant structures. Mass spectrometry-based approaches for biomacromolecule structural characterization are growing, beginning to fill critical gaps, complement other biology tools. We have shown several examples that collision ions with surface yields products reflective substructure. present here computational model predicts relative appearance energy at which globular...
Covalent labeling (CL) in combination with mass spectrometry can be used as an analytical tool to study and determine structural properties of protein-protein complexes. However, data from these experiments is sparse does not unambiguously elucidate protein structure. Thus, computational algorithms are needed deduce structure the CL data. In this work, we present a hybrid method that combines models complex subunits generated AlphaFold differential via CL-guided docking Rosetta. benchmark...
With the rise in resistance to antibiotics such as methicillin, there is a need for new drugs. We report here discovery and X-ray crystallographic structures of 10 chemically diverse compounds (benzoic, diketo, phosphonic acids, well bisamidine bisamine) that inhibit bacterial undecaprenyl diphosphate synthase, an essential enzyme involved cell wall biosynthesis. The inhibitors bind one or more four synthase inhibitor binding sites identified previously, with most active leads site 4,...
Electron density maps of membrane proteins or large macromolecular complexes are frequently only determined at medium resolution between 4 Å and 10 Å, either by cryo-electron microscopy X-ray crystallography. In these maps, the general arrangement secondary structure elements (SSEs) is revealed, whereas their directionality connectivity remain elusive. We demonstrate that topology with up to 250 amino acids can be from such when combined a computational protein folding protocol. Furthermore,...
Abstract Hydroxyl radical protein footprinting (HRPF) in combination with mass spectrometry reveals the relative solvent exposure of labeled residues within a protein, thereby providing insight into tertiary structure. HRPF labels nineteen varying degrees reliability and reactivity. Here, we are presenting dynamics-driven HRPF-guided algorithm for structure prediction. In benchmark test our algorithm, usage dynamics data score term resulted notable improvement root-mean-square deviations...
Abstract Ion mobility (IM) mass spectrometry provides structural information about protein shape and size in the form of an orientationally-averaged collision cross-section (CCS IM ). While data have been used with various computational methods, they not yet utilized to predict monomeric structure from sequence. Here, we show that can significantly improve determination using modelling suite Rosetta. We develop Rosetta Projection Approximation Rough Circular Shapes (PARCS) algorithm allows...
In recent years mass spectrometry-based covalent labeling techniques such as hydroxyl radical footprinting (HRF) have emerged valuable structural biology techniques, yielding information on protein tertiary structure. These data, however, are not sufficient to predict structure unambiguously, they provide only the relative solvent exposure of certain residues. Despite some advances, no software currently exists that can utilize spectrometry data We developed first tool, which incorporates...
Macrocyclic peptides are capable of binding to flat protein surfaces such as the interfaces protein-protein interactions with antibody-like affinity and specificity, but generally lack cell permeability in order access intracellular targets. In this work, we designed synthesized a large combinatorial library cell-permeable bicyclic peptides, which first ring consisted randomized peptide sequences for potential target interest, while second featured family different cell-penetrating motifs,...
Recently, mass spectrometry (MS) has become a viable method for elucidation of protein structure. Surface-induced dissociation (SID), colliding multiply charged complexes or other ions with surface, been paired native MS to provide useful structural information such as connectivity and topology many different complexes. We recently showed that SID gives not only on but also relative interface strengths. However, yet coupled computational structure prediction methods could use the sparse from...
Native Mass Spectrometry (nMS) is a versatile technique for elucidating protein structure. Surface-Induced Dissociation (SID) an activation method in tandem MS predominantly employed determining complex stoichiometry alongside information about interface strengths. SID-nMS data can be collected over range of acceleration energies, yielding Energy Resolved (ERMS) data. Previous work demonstrated that the onset and appearance energy from used integrative computational experimental modeling to...
The structure of the adenovirus type 2 temperature-sensitive mutant 1 (Ad2ts1) was determined to a resolution 10 A by cryo-electron microscopy single-particle reconstruction. Ad2ts1 prepared at nonpermissive temperature and contains precursor forms capsid proteins IIIa, VI, VIII; core VII, X (mu), terminal protein (TP); L1-52K protein. Cell entry studies have shown that although can bind coxsackievirus Ad receptor undergo internalization via alphav integrins, this does not escape from early...
A structure of adenovirus type 12 (HAdV12) complexed with a soluble form integrin alphavbeta5 was determined by cryo-electron microscopy (cryoEM) image reconstruction. Subnanometer resolution (8 A) achieved for the icosahedral capsid moderate (27 density above each penton base. Modeling alphavbeta3 and alpha(IIb)beta3 crystal structures indicates that maximum four integrins fit over pentameric The close spacing (approximately 60 RGD protrusions on base precludes binding in same orientation...
We here present an improved version of AutoGrow (version 3.0), evolutionary algorithm that works in conjunction with existing open-source software to automatically optimize candidate ligands for predicted binding affinity and other druglike properties. Though no substitute the medicinal chemist, 3.0, unlike its predecessors, attempts introduce some chemical intuition into automated optimization process. 3.0 uses rules click chemistry guide optimization, greatly enhancing synthesizability....