A5082022500- Lipid Membrane Structure and Behavior
- Protein Structure and Dynamics
- X-ray Diffraction in Crystallography
- Antibiotic Resistance in Bacteria
- Crystallization and Solubility Studies
- Glycosylation and Glycoproteins Research
- HIV Research and Treatment
- Bacterial Genetics and Biotechnology
- Enzyme Structure and Function
- Monoclonal and Polyclonal Antibodies Research
- Bacteriophages and microbial interactions
- Protein Kinase Regulation and GTPase Signaling
- Metal complexes synthesis and properties
- Immune Cell Function and Interaction
- Computational Drug Discovery Methods
- Endoplasmic Reticulum Stress and Disease
- Crystallography and molecular interactions
- T-cell and B-cell Immunology
- Advanced Cellulose Research Studies
- Biofuel production and bioconversion
- Crystal structures of chemical compounds
- Lipid metabolism and biosynthesis
- Drug Transport and Resistance Mechanisms
- Inorganic Chemistry and Materials
- Lanthanide and Transition Metal Complexes
Los Alamos National Laboratory
2015-2024
Hudson Institute
2023
John Wiley & Sons (Germany)
2023
Moss Landing Marine Laboratories
2023
New York Academy of Sciences
2023
Universitat Politècnica de València
2022
University of New Mexico
2022
National University Toribio Rodríguez de Mendoza
2022
Hospital Juárez de México
2020
University of Groningen
2009-2019
The detailed organization of cellular membranes remains rather elusive. Based on large-scale molecular dynamics simulations, we provide a high-resolution view the lipid plasma membrane at an unprecedented level complexity. Our model consists 63 different species, combining 14 types headgroups and 11 tails asymmetrically distributed across two leaflets, closely mimicking idealized mammalian membrane. We observe enrichment cholesterol in outer leaflet general non-ideal lateral mixing species....
Computational modeling of biological systems is challenging because the multitude spatial and temporal scales involved. Replacing atomistic detail with lower resolution, coarse grained ( CG ), beads has opened way to simulate large‐scale biomolecular processes on time inaccessible all‐atom models. We provide an overview some more popular models used in applications date, focusing that retain chemical specificity. A few state‐of‐the‐art examples protein folding, membrane gating self‐assembly,...
Gram-negative bacteria are intrinsically resistant to many antibiotics. Species that have acquired multidrug resistance and cause infections effectively untreatable present a serious threat public health. The problem is broadly recognized tackled at both the fundamental applied levels. This paper summarizes current advances in understanding molecular bases of low permeability barrier pathogens, which major obstacle discovery development antibiotics effective against such pathogens. Gaps...
We present an extension of the Martini coarse-grained force field to carbohydrates. The parametrization follows same philosophy as was used previously for lipids and proteins, focusing on reproduction partitioning free energies small compounds between polar nonpolar phases. carbohydrate building blocks considered are monosaccharides glucose fructose disaccharides sucrose, trehalose, maltose, cellobiose, nigerose, laminarabiose, kojibiose, sophorose. Bonded parameters these saccharides...
Major histocompatibility complex E (MHC-E) is a highly conserved, ubiquitously expressed, nonclassical MHC class Ib molecule with limited polymorphism that primarily involved in the regulation of natural killer (NK) cells. We found vaccinating rhesus macaques cytomegalovirus vectors which genes Rh157.5 and Rh157.4 are deleted results MHC-E-restricted presentation varied peptide epitopes to CD8αβ(+) T cells, at ~4 distinct per 100 amino acids all tested antigens. Computational structural...
The depletion of cholesterol from membranes, mediated by β-cyclodextrin (β-CD) is well known and documented, but the molecular details this process are largely unknown. Using dynamics simulations, we have been able to study CD extraction model in particular a pure monolayer, at atomic resolution. Our results show that efficient depends on structural distribution CDs surface monolayer. With suitably oriented dimer, extracted spontaneously nanosecond time scale. Additional free energy...
We present an extension of the Martini coarse-grained force field to glycolipids. The glycolipids considered here are glycoglycerolipids monogalactosyldiacylglycerol (MGDG), sulfoquinovosyldiacylglycerol (SQDG), digalactosyldiacylglycerol (DGDG), and phosphatidylinositol (PI) its phosphorylated forms (PIP, PIP2), as well glycosphingolipids galactosylceramide (GCER) monosialotetrahexosylganglioside (GM1). parametrization follows same philosophy was used previously for lipids, proteins,...
Glucansucrases are large enzymes belonging to glycoside hydrolase family 70, which catalyze the cleavage of sucrose into fructose and glucose, with concomitant transfer glucose residue a growing α-glucan polymer. Among others, plaque-forming oral bacteria secrete these produce α-glucans, facilitate adhesion tooth enamel. We determined crystal structure fully active, 1,031-residue fragment encompassing catalytic C-terminal domains GTF180 from Lactobacillus reuteri 180, both in native state,...
Beta-cyclodextrins (β-CDs) can form inclusion complexes with cholesterol, and are commonly used to manipulate cholesterol levels of biomembranes. In this work, we have multiscale molecular dynamics simulations provide a detailed view on the interaction between β-CDs lipid model membranes. We show that be extracted efficiently upon adsorption β-CD dimers at membrane/water interface. However, extraction is only observed occur spontaneously in membranes high levels. Free energy calculations...
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...
We present results from coarse grain molecular dynamics simulations of mixed model membranes consisting saturated and unsaturated lipids together with cholesterol, in which lipid-anchored membrane proteins are embedded. The studied the peripherally bound H-Ras, N-Ras, Hedgehog, transmembrane peptides WALP LAT. provide a view on how presence nature these lipid anchors affects partitioning between liquid-ordered liquid-disordered domains. In addition, we probed role ganglioside GM1 protein...
Whether lipid rafts are present in the membranes of living cells remains hotly disputed despite their incontrovertible existence liposomes at 298 K. In attempts to resolve this debate, molecular dynamics (MD) simulations have been extensively used study phase separation high resolution. However, computation has limited utility respect because experimental distributions phases lamellar mixtures poorly reproduced by simulations. particular, all-atom (AA) approaches suffer from restrictions on...
The dense array of N-linked glycans on the HIV-1 envelope glycoprotein (Env), known as "glycan shield," is a key determinant immunogenicity, yet intrinsic heterogeneity confounds typical structure-function analysis. Here, we present an integrated approach single-particle electron cryomicroscopy (cryo-EM), computational modeling, and site-specific mass spectrometry (MS) to probe glycan shield structure behavior at multiple levels. We found that dynamics lead extensive network interglycan...
Interdependence across time and length scales is common in biology, where atomic interactions can impact larger-scale phenomenon. Such dependence especially true for a well-known cancer signaling pathway, the membrane-bound RAS protein binds an effector called RAF. To capture driving forces that bring RAF (represented as two domains, RBD CRD) together on plasma membrane, simulations with ability to calculate detail while having long large length- are needed. The Multiscale Machine-Learned...
Abstract The oncogene RAS, extensively studied for decades, presents persistent gaps in understanding, hindering the development of effective therapeutic strategies due to a lack precise details on how RAS initiates MAPK signaling with RAF effector proteins at plasma membrane. Recent advances X-ray crystallography, cryo-EM, and super-resolution fluorescence microscopy offer structural spatial insights, yet molecular mechanisms involving protein-protein protein-lipid interactions RAS-mediated...
Commercial-scale biofuel production requires a deep understanding of the structure and dynamics its principal target: cellulose. However, an accurate description modeling this carbohydrate at mesoscale remains elusive, particularly because overwhelming length scale configurational complexity. We have derived set MARTINI coarse-grained force field parameters for simulation crystalline cellulose fibers. The model is adapted to reproduce different physicochemical mechanical properties native...
Disaccharides are well-known for their membrane protective ability. Interaction between sugars and multicomponent membranes, however, remains largely unexplored. Here, we combine molecular dynamics simulations fluorescence microscopy to study the effect of mono- disaccharides on membranes that phase separate into Lo Ld domains. We find nonreducing disaccharides, sucrose trehalose, strongly destabilize separation leading uniformly mixed as opposed monosaccharides reducing disaccharides. To...
Significance The proto-oncogene KRAS , a small GTPase, is frequently mutated in pancreatic, colorectal, and lung cancer. These mutations result elevated levels of the activated guanosine triphosphate-bound form KRAS. Localized at plasma membrane, functions to recruit effectors, predominantly RAF kinase for activation initiation MAPK signaling cascade. Combining computational biophysical methods we identify membrane-distal state G-domain that alternates with two previously described...
Efflux pump avoidance and inhibition are desired properties for the optimization of antibacterial activities against Gram-negative bacteria. However, molecular physicochemical interactions defining interface between compounds efflux pumps remain poorly understood. We identified that correlate with inhibition, predictive similar features in structurally diverse compounds, allow researchers to distinguish substrates, inhibitors, avoiders P. aeruginosa .
Protein–membrane interactions (PMIs) are ubiquitous in cellular signaling. Initial steps of signal transduction cascades often rely on transient and dynamic with the inner plasma membrane leaflet to populate regulate signaling hotspots. Methods target modulate these could yield attractive tool compounds drug candidates. Here, we demonstrate that conjugation a medium-chain lipid tail covalent K-Ras(G12C) binder MRTX849 at solvent-exposed site enables such direct modulation PMIs. The...