A5081875245- Glycosylation and Glycoproteins Research
- Protein Structure and Dynamics
- RNA and protein synthesis mechanisms
- Monoclonal and Polyclonal Antibodies Research
- Carbohydrate Chemistry and Synthesis
- Enzyme Structure and Function
- Microbial Natural Products and Biosynthesis
- Chemical Synthesis and Analysis
- Genetics, Bioinformatics, and Biomedical Research
- Genomics and Phylogenetic Studies
- Antibiotic Resistance in Bacteria
- Scientific Computing and Data Management
- Computational Drug Discovery Methods
- Peptidase Inhibition and Analysis
- Galectins and Cancer Biology
- Distributed and Parallel Computing Systems
- Enzyme Production and Characterization
- Ubiquitin and proteasome pathways
- Advanced Proteomics Techniques and Applications
- Fungal and yeast genetics research
- Fungal Biology and Applications
- Biochemical and Structural Characterization
- Renin-Angiotensin System Studies
- Adenosine and Purinergic Signaling
- Machine Learning in Bioinformatics
Notre Dame of Maryland University
2025
Johns Hopkins University
2012-2024
Franklin & Marshall College
2019-2021
Gettysburg College
2020-2021
Over the past decade, Rosetta biomolecular modeling suite has informed diverse biological questions and engineering challenges ranging from interpretation of low-resolution structural data to design nanomaterials, protein therapeutics, vaccines. Central Rosetta's success is energy function: a model parametrized small-molecule X-ray crystal structure used approximate associated with each biomolecule conformation. This paper describes mathematical models physical concepts that underlie latest...
Mutations are central to evolution, providing the genetic variation upon which selection acts. A mutation's effect on suitability of a gene perform particular function (gene fitness) can be positive, negative, or neutral. Knowledge distribution fitness effects (DFE) mutations is fundamental for understanding evolutionary dynamics, molecular-level variation, complex disease, accumulation deleterious mutations, and molecular clock. We present comprehensive DFEs point codon mutants Escherichia...
Carbohydrates and glycoproteins modulate key biological functions. However, experimental structure determination of sugar polymers is notoriously difficult. Computational approaches can aid in carbohydrate prediction, determination, design. In this work, we developed a glycan-modeling algorithm, GlycanTreeModeler, that computationally builds glycans layer-by-layer, using adaptive kernel density estimates (KDE) common glycan conformations derived from data the Protein Data Bank (PDB) quantum...
Significance Peptide macrocycles are a promising class of drugs, but their weakness is conformational flexibility: target affinity can be limited by an unfavorable transition from disordered unbound state to ordered bound state. We introduce general computational methods for stabilizing peptide in binding-competent conformations as part the process designing binding protein. As proof principle, we apply our create inhibitors New Delhi metallo-β-lactamase 1, antibiotic resistance factor....
Polyketide natural products possess diverse architectures and biological functions share a subset of biosynthetic steps with fatty acid synthesis. The final transformation catalyzed by both polyketide synthases (PKSs) is most often carried out thioesterase (TE). synthetic versatility TE domains in fungal nonreducing, iterative PKSs (NR-PKSs) has been shown to extend Claisen cyclase (CLC) chemistry catalyzing C–C ring closure reactions as opposed thioester hydrolysis or O–C/N–C...
Abstract Over the past decade, Rosetta biomolecular modeling suite has informed diverse biological questions and engineering challenges ranging from interpretation of low-resolution structural data to design nanomaterials, protein therapeutics, vaccines. Central Rosetta’s success is energy function: amodel parameterized small molecule X-ray crystal structure used approximate associated with each biomolecule conformation. This paper describes mathematical models physical concepts that...
Peptidomimetics are classes of molecules that mimic structural and functional attributes polypeptides. Peptidomimetic oligomers can frequently be synthesized using efficient solid phase synthesis procedures similar to peptide synthesis. Conformationally ordered peptidomimetic finding broad applications for molecular recognition inhibiting protein-protein interactions. One critical limitation is the limited set design tools identifying oligomer sequences adopt desired conformations. Here, we...
The RosettaCarbohydrate framework is a new tool for modeling wide variety of saccharide and glycoconjugate structures. This report describes the development highlights its applications. integrates with established protocols within Rosetta design suite, it handles vast complexity carbohydrate molecules, including branching sugar modifications. To address challenges sampling scoring, can sample glycosidic bonds, side‐chain conformations, ring forms, utilizes glycan‐specific term scoring...
Abstract N ‐Methylation of the peptide backbone confers pharmacologically beneficial characteristics to peptides that include greater membrane permeability and resistance proteolytic degradation. The borosin family ribosomally synthesized post‐translationally modified offer a post‐translational route install amide α‐ ‐methylations. Previous work has elucidated substrate scope engineering potential two examples type I borosins, which feature autocatalytic precursors encode ‐methyltransferases...
Abstract Cyclic symmetry is frequent in protein and peptide homo‐oligomers, but extremely rare within a single chain, as it not compatible with free N‐ C‐termini. Here we describe the computational design of mixed‐chirality macrocycles rigid structures that feature internal cyclic symmetries or improper rotational inaccessible to natural proteins. Crystal three C2‐ C3‐symmetric macrocycles, six diverse S2‐symmetric match computationally‐designed models backbone heavy‐atom RMSD values 1 Å...
Each year vast international resources are wasted on irreproducible research. The scientific community has been slow to adopt standard software engineering practices, despite the increases in high-dimensional data, complexities of workflows, and computational environments. Here we show how applications can be created a reproducible manner when simple design goals for reproducibility met. We describe implementation test server framework 40 benchmarks, covering numerous Rosetta...
Abstract Carbohydrates and glycoproteins modulate key biological functions. Computational approaches inform function to aid in carbohydrate structure prediction, determination, design. However, experimental determination of sugar polymers is notoriously difficult as glycans can sample a wide range low energy conformations, thus limiting the study glycan-mediated molecular interactions. In this work, we expanded RosettaCarbohydrate framework, developed benchmarked effective tools for glycan...
Carbohydrate chains are ubiquitous in the complex molecular processes of life. These highly diverse recognized by a variety protein receptors, enabling glycans to regulate many biological functions. High-resolution structures protein-glycoligand complexes reveal atomic details necessary understand this level recognition and inform application-focused scientific engineering pursuits. When experimental challenges hinder high-throughput determination quality structures, computational tools can,...
Significance Asparagine-linked ( N -linked) protein glycosylation—the covalent attachment of complex sugars to the nitrogen atom in asparagine side chains—is most widespread posttranslational modification proteins and also complex. N- glycosylation affects a significant number cellular can have profound effects on their important attributes such as biological activity, chemical solubility, folding stability, immunogenicity, serum half-life. Accordingly, strategic installation glycans at...
ABSTRACT Rounds 20–27 of the Critical Assessment PRotein Interactions (CAPRI) provided a testing platform for computational methods designed to address wide range challenges. The diverse targets drove creation and new combinations tools. In this study, RosettaDock other novel Rosetta protocols were used successfully predict four 10 blind targets. For example, DNase domain Colicin E2–Im2 immunity protein, RosettaLigand positions water molecules at interface, recovering 46% native...
Nitroxyl (HNO), a potential heart failure therapeutic, is known to post-translationally modify cysteine residues. Among reactive nitrogen oxide species, the modification of residues sulfinamides [RS(O)NH2] unique HNO. We have applied (15)N-edited (1)H NMR techniques detect HNO-induced thiol sulfinamide in several small organic molecules, peptides, and protease, papain. Relevant reactions involve reduction free thiols presence excess hydrolysis form sulfinic acids [RS(O)OH]. investigated at...
Including undergraduate research in STEM education is a well-supported and growing high-impact practice that has been made much more scalable through integrating these experiences into the classroom. Here we describe new biochemistry Course-based Undergraduate Research Experience (CURE) follows design-to-data workflow with strong connection to worldwide community of protein modeling software developers. Analysis psychosocial developments association participating this CURE from first set...
Abstract Critical Assessment of PRediction Interactions (CAPRI) rounds 37 through 45 introduced larger complexes, new macromolecules, and multistage assemblies. For these rounds, we used expanded docking methods in Rosetta to model 23 target complexes. We successfully predicted 14 complexes recognized refined near‐native models generated by other groups for two further targets. Notably, targets T110 T136, achieved the closest prediction any CAPRI participant. created several innovative...