A5001257836- Protein Structure and Dynamics
- Protein Kinase Regulation and GTPase Signaling
- Cellular Mechanics and Interactions
- Endoplasmic Reticulum Stress and Disease
- Nicotinic Acetylcholine Receptors Study
- Antibiotic Resistance in Bacteria
- Computational Drug Discovery Methods
- Rheumatoid Arthritis Research and Therapies
- Genetics and Physical Performance
- Heat shock proteins research
- Bacterial Genetics and Biotechnology
- Microbial Natural Products and Biosynthesis
- Enzyme Structure and Function
- Clostridium difficile and Clostridium perfringens research
- Cardiomyopathy and Myosin Studies
- Chemical Synthesis and Analysis
- Lipid Membrane Structure and Behavior
- Receptor Mechanisms and Signaling
- Drug Transport and Resistance Mechanisms
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Calpain Protease Function and Regulation
- Advanced Fluorescence Microscopy Techniques
- CO2 Sequestration and Geologic Interactions
- Gene Regulatory Network Analysis
- Cell Image Analysis Techniques
Los Alamos National Laboratory
2017-2022
New Mexico Consortium
2020
University of Pittsburgh
2013-2016
Activation of RAF kinase involves the association its RAS-binding domain (RBD) and cysteine-rich (CRD) with membrane-anchored RAS. However, overall architecture RAS/RBD/CRD ternary complex orientations constituent domains at membrane remain unclear. Here, we have combined all-atom coarse-grained molecular dynamics (MD) simulations experimental data to construct validate a model CRD, used this as basis explore models complex. First, CRD revealed that it anchors via insertion two hydrophobic...
Significance Here we present an unprecedented multiscale simulation platform that enables modeling, hypothesis generation, and discovery across biologically relevant length time scales to predict mechanisms can be tested experimentally. We demonstrate our predictive simulation-experimental validation loop generates accurate insights into RAS-membrane biology. Evaluating over 100,000 correlated simulations, show RAS–lipid interactions are dynamic evolving, resulting in: 1) a reordering...
Antibiotic efflux is one of the most critical mechanisms leading to bacterial multidrug resistance. Antibiotics are effluxed out cell by a tripartite pump, complex machinery comprised outer membrane, periplasmic adaptor, and inner membrane protein components. Understanding mechanism pump assembly its dynamics could facilitate discovery novel approaches counteract antibiotic resistance in bacteria. We built here an intact atomistic model Pseudomonas aeruginosa MexAB-OprM Gram-negative that...
Abstract Post-translational protein modifications such as citrullination have been linked to the breach of immune tolerance and clinical autoimmunity. Previous studies from our laboratory support this concept, demonstrating that autoantibodies targeting citrullinated isoforms heat shock 90 (HSP90) are associated with rheumatoid arthritis complicated by interstitial lung disease. To further explore relationship between structural determinants HSP90 immunogenicity, we employed a combination...
Phosphorylated residues occur preferentially in the intrinsically disordered regions of eukaryotic proteins. In amino-terminal region human α-actinin-4 (ACTN4), Tyr(4) and Tyr(31) are phosphorylated cells stimulated with epidermal growth factor (EGF), a mutant phosphorylation-mimicking mutations both tyrosines exhibits reduced interaction actin vitro. Cleavage ACTN4 by m-calpain, protease that motile is predominantly activated at rear, removes site. We found introducing phosphomimetic...
The assembly of proteins into multidomain complexes is critical for their function. In eukaryotic nonmuscle cells, regulation the homodimeric actin cross-linking protein α-actinin-4 (ACTN4) during cell migration involves signaling receptors with intrinsic tyrosine kinase activity, yet underlying molecular mechanisms are poorly understood. As a first step to address latter, we validate here an atomic model ACTN4 end region, which corresponds ternary complex between N-terminal actin-binding...
Syk/Zap70 family kinases are essential for signaling via multichain immune-recognition receptors such as tetrameric (αβγ2) FcεRI. Syk activation is generally attributed to cis binding of its tandem SH2 domains dual phosphotyrosines within FcεRIγ-ITAMs (immunoreceptor tyrosine-based motifs). However, the mechanistic details docking on γ homodimers unresolved. Here, we estimate that multivalent interactions WT improve cis-oriented by three orders magnitude. We applied molecular dynamics (MD),...
Conotoxins are short, cysteine-rich peptides of great interest as novel therapeutic leads and concern lethal biological agents due to their high affinity specificity for various receptors involved in neuromuscular transmission. Currently, the approximately 6000 known conotoxin sequences, only about 3% have associated structural characterization, which a bottleneck rapid high-throughput screening (HTS) identification potential or threats. In this work, we combine graph-based approach with...
Abstract RAS is a signaling protein associated with the cell membrane that mutated in 30% of human cancers. has been proposed to be regulated by dynamic heterogeneity membrane. Investigating such mechanism requires near-atomic detail at macroscopic temporal and spatial scales, which not possible conventional computational or experimental techniques. We demonstrate here multiscale simulation infrastructure uses machine learning create scale-bridging ensemble over 100,000 simulations active...
Knowledge of the 3D structure and functionality proteins can lead to insight into associated cellular processes, speed up creation pharmaceutical products, develop drugs that are more effective in combating disease. We present design implementation a visual mining analysis tool help identify protein mutations across family structural models discover effect these on function. integrate sequence information common interface; multiple linked views computational backbone allow comparison at...
ABSTRACT Syk/Zap70 family kinases are essential for signaling via multichain immune-recognition receptors such as the tetrameric (αβγ2) FcεRI The simplest model assumes that Syk activation occurs through cis binding of its tandem SH2 domains to dual phosphotyrosines within immunoreceptor tyrosine-based motifs individual γ chains. In this model, activity is modulated by phosphorylation occurring between adjacent molecules docked on homodimers and Lyn bound FcεRIβ. However, mechanistic details...
Abstract Driver mutations in KRAS occur almost 30% of human tumors, primarily pancreatic, colorectal and lung tumors. These result increased cell proliferation survival predominantly mediated through the MAPK signaling pathway. signal transduction is initiated by interaction RAF kinase with active RAS at plasma membrane. The precise molecular details this process are currently unknown. Frederick National Laboratory for Cancer Research has partnered Department Energy to harness...
Many toxins are short, cysteine-rich peptides that of great interest as novel therapeutic leads and concern lethal biological agents due to their high affinity specificity for various receptors involved in neuromuscular transmission. To perform initial candidate identification design a drug impacting particular receptor or threat assessment harmful toxin, one requires set structures reasonable accuracy with potential interaction the target receptor. In this article, we introduce graph-based...