A5041863732- Protein Structure and Dynamics
- Monoclonal and Polyclonal Antibodies Research
- Chemical Synthesis and Analysis
- Glycosylation and Glycoproteins Research
- Lipid Membrane Structure and Behavior
- Enzyme Structure and Function
- Spectroscopy and Quantum Chemical Studies
- RNA and protein synthesis mechanisms
- Peptidase Inhibition and Analysis
- Plant biochemistry and biosynthesis
- Blood Coagulation and Thrombosis Mechanisms
- CRISPR and Genetic Engineering
- Microbial Metabolic Engineering and Bioproduction
- Pesticide and Herbicide Environmental Studies
- Computational Drug Discovery Methods
- Photosynthetic Processes and Mechanisms
- Blood properties and coagulation
- Pesticide Exposure and Toxicity
- Hemophilia Treatment and Research
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Biotin and Related Studies
- ATP Synthase and ATPases Research
- Trace Elements in Health
- Protein purification and stability
- Protease and Inhibitor Mechanisms
Novo Nordisk (Denmark)
2017-2024
Novo Nordisk (United States)
2021-2024
Digital Science (United States)
2024
Seattle University
2017-2023
University of Washington
2013-2021
Zymergen (United States)
2021
enEvolv (United States)
2019-2021
ENVIRON (United States)
2019
Technical University of Denmark
2008-2014
Most biomolecular modeling energy functions for structure prediction, sequence design, and molecular docking have been parametrized using existing macromolecular structural data; this contrasts mechanics force fields which are largely optimized small-molecule data. In study, we describe an integrated method that enables optimization of a function simultaneously against thermodynamic data high-resolution We use approach to develop next-generation Rosetta utilizes new anisotropic implicit...
Abstract Substrate inhibition of enzymes can be a major obstacle to the production valuable chemicals in engineered microorganisms. Here, we show substrate lycopene cyclase as main limitation carotenoid biosynthesis Yarrowia lipolytica . To overcome this bottleneck, exploit two independent approaches. Structure-guided protein engineering yields variant, Y27R, characterized by complete loss without reduction enzymatic activity. Alternatively, establishing geranylgeranyl pyrophosphate...
We describe the computational design of proteins that bind potent analgesic fentanyl. Our approach employs a fast docking algorithm to find shape complementary ligand placement in protein scaffolds, followed by surrounding residues optimize binding affinity. Co-crystal structures highest affinity binder reveal highly preorganized site, and an overall architecture close agreement with model. use designs generate plant sensors for fentanyl coupling stability. The method should be generally...
VX and its Russian (RVX) Chinese (CVX) analogues rapidly inactivate acetylcholinesterase are the most toxic stockpile nerve agents. These organophosphates have a thiol leaving group with choline-like moiety hydrolyzed very slowly by natural enzymes. We used an integrated computational experimental approach to increase Brevundimonas diminuta phosphotriesterase's (PTE) detoxification rate of V-agents 5000-fold. Computational models were built complex between PTE V-agents. On basis these...
In phenylketonuria (PKU) patients, a genetic defect in the enzyme phenylalanine hydroxylase (PAH) leads to elevated systemic (Phe), which can result severe neurological impairment. As treatment for PKU, Escherichia coli Nissle (EcN) strain SYNB1618 was developed under Synlogic's Synthetic Biotic™ platform degrade Phe from within gastrointestinal (GI) tract. This clinical-stage engineered expresses Phe-metabolizing ammonia lyase (PAL), catalyzing deamination of non-toxic product...
Despite recent success in computational design of structured cyclic peptides, de novo peptides that bind to any protein functional site remains difficult. To address this challenge, we develop a "anchor extension" methodology for targeting interfaces by extending peptide chain around non-canonical amino acid residue anchor. test our approach using well characterized model system, inhibit histone deacetylases 2 and 6 (HDAC2 HDAC6) with enhanced potency compared the original anchor (IC
Improving an enzyme's initially low catalytic efficiency with a new target substrate by order of magnitude or two may require only few rounds mutagenesis and screening selection. However, subsequent optimization tend to yield decreasing degrees improvement (diminishing returns) eventually leading plateau. We aimed optimize the bacterial phosphotriesterase (PTE) toward V-type nerve agents. Previously, we improved wild-type PTE agent VX 500-fold, (kcat/KM) 5 × 106 M−1 min−1. effective in vivo...
The steroid hormone 17α-hydroxylprogesterone (17-OHP) is a biomarker for congenital adrenal hyperplasia and hence there considerable interest in development of sensors this compound. We used computational protein design to generate models with binding sites 17-OHP containing an extended, nonpolar, shape-complementary pocket the four-ring core compound, hydrogen bonding residues at base interact carbonyl hydroxyl groups more polar end ligand. Eight 16 designed proteins experimentally tested...
Linear rate-equilibrium (RE) relations, also known as linear free energy are widely observed in chemical reactions, including protein folding, enzymatic catalysis, and channel gating. Despite the widespread occurrence of RE principles underlying relation between changes activation equilibrium macromolecular reactions remain enigmatic. When examining amphiphile regulation gramicidin gating lipid bilayers, we noted that process could be described by a with simple geometric interpretation. This...
Endocytosis and lysosomal trafficking of cell surface receptors can be triggered by interaction with endogenous ligands. Therapeutic approaches such as LYTAC
Aggregation can be a major challenge in the development of antibody-based pharmaceuticals as it compromise quality product during bioprocessing, formulation, and drug administration. To avoid aggregation, developability assessment is often run parallel with functional optimization early screening phases to flag deselect problematic molecules. As demanding regard time resources, there high focus on molecule design strategies for engineering molecules potential. Previously, Dudgeon et al....
Abstract Single‐chain variable fragments (scFv) are widely used in several fields. However, they can be challenging to purify unless using expensive Protein L‐based affinity adsorbents or tags. In this work, a purification process for scFv mixed‐mode (MM) chromatography was developed by design of experiments (DoE) and proteomics host cell protein (HCP) quantification. Capture from human embryonic kidney 293 (HEK293) feedstocks performed hydrophobic charge induction (MEP HyperCel™),...
Phosphorus is a ubiquitous element of the cell, which found throughout numerous key molecules related to cell structure, energy and information storage transfer, diverse array other cellular functions. In this work, we adopt an approach often used for characterizing metal binding selectivity metalloproteins in terms interactions first shell (direct residue with metal) second (residue residues) use it characterize phosphorus compounds. Similar analyses have previously been limited individual...
Abstract Antibody-based therapies are at the forefront of modern medicine, addressing diverse challenges across oncology, autoimmune diseases, infectious and beyond. The ability to design antibodies with enhanced functionality specificity is critical for advancing next-generation therapeutics. Recent advances in artificial intelligence (AI) have propelled field antibody engineering, particularly through inverse folding models Complementarity-Determining Region (CDR) sequence design. These...