A5032644017- Lipid Membrane Structure and Behavior
- Protein Structure and Dynamics
- RNA and protein synthesis mechanisms
- Spectroscopy and Quantum Chemical Studies
- Hedgehog Signaling Pathway Studies
- Glycosylation and Glycoproteins Research
- Cholesterol and Lipid Metabolism
- Mass Spectrometry Techniques and Applications
- Bacterial Genetics and Biotechnology
- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Genomics and Chromatin Dynamics
- Mycorrhizal Fungi and Plant Interactions
- Advanced Electron Microscopy Techniques and Applications
- Kruppel-like factors research
- Drug Transport and Resistance Mechanisms
- Cancer-related Molecular Pathways
- Advanced Fluorescence Microscopy Techniques
- Forest Ecology and Biodiversity Studies
- Fractal and DNA sequence analysis
- Pancreatic function and diabetes
- Diabetes Treatment and Management
- Force Microscopy Techniques and Applications
- Epigenetics and DNA Methylation
- Machine Learning in Bioinformatics
University of Oxford
2019-2025
Stanford University
2024-2025
SLAC National Accelerator Laboratory
2024
Stanford Synchrotron Radiation Lightsource
2024
Swansea University
2024
Materials Science & Engineering
2024
Centre for Human Genetics
2023
Lipids play important modulatory and structural roles for membrane proteins. Molecular dynamics simulations are frequently used to provide insights into the nature of these protein-lipid interactions. Systematic comparative analysis requires tools that algorithms objective assessment such We introduce PyLipID, a Python package identification characterization specific lipid interactions binding sites on proteins from molecular simulations. PyLipID uses community approach site detection,...
This study uses MD simulations to identify and analyze >700 binding sites for cardiolipin a set of bacterial membrane proteins.
Smoothened (SMO) transduces the Hedgehog (Hh) signal across plasma membrane in response to accessible cholesterol. Cholesterol binds SMO at two sites: one extracellular cysteine-rich domain (CRD) and a second transmembrane (TMD). How these sterol-binding sites mediate activation ligand Sonic (SHH) remains unknown. We find that mutations CRD (but not TMD) reduce fold increase activity triggered by SHH. SHH also promotes photocrosslinking of sterol analog intact cells. In contrast, binding TMD...
The Sonic Hedgehog (SHH) morphogen pathway is fundamental for embryonic development and stem cell maintenance implicated in various cancers. A key step signaling transfer of a palmitate group to the SHH N terminus, catalyzed by multi-pass transmembrane enzyme acyltransferase (HHAT). We present high-resolution cryo-EM structure HHAT bound substrate analog palmityl-coenzyme SHH-mimetic megabody, revealing heme that essential function. potent small-molecule inhibitor IMP-1575 revealed...
Cryo-electron microscopy (cryo-EM) enables the determination of membrane protein structures in native-like environments. Characterising how proteins interact with surrounding lipid environment is assisted by resolution lipid-like densities visible cryo-EM maps. Nevertheless, establishing molecular identity putative and/or detergent remains challenging. Here we present LipIDens, a pipeline for dynamics (MD) simulation-assisted interpretation and structures. The integrates implementation...
Most of Earth's trees rely on critical soil nutrients that ectomycorrhizal fungi (EcMF) liberate and provide, all land plants associate with bacteria help them survive in nature. Yet, our understanding how the presence EcMF modifies bacterial communities, food webs, root chemistry requires direct experimental evidence to comprehend effects may generate belowground plant microbiome. To this end, we grew
Specific interactions of lipids with membrane proteins contribute to protein stability and function. Multiple lipid surrounding a are often identified in molecular dynamics (MD) simulations are, increasingly, resolved cryo-electron microscopy (cryo-EM) densities. Determining the relative importance specific interaction sites is aided by determination binding affinities using experimental or simulation methods. Here, we develop method for determining protein-lipid from equilibrium...
The extracellular domain (ECD) of class B1 G-protein-coupled receptors (GPCRs) plays a central role in signal transduction and is uniquely positioned to sense both the membrane environments. Although recent studies suggest for lipids modulation A F GPCR signaling properties, little known about effect on receptors. In this study, we employed multiscale molecular dynamics simulations access glucagon receptor (GCGR) ECD presence native-like bilayers. Simulations showed that could move hinge...
In Gram-negative bacteria, the enzymatic modification of Lipid A with aminoarabinose (L-Ara4N) leads to resistance against polymyxin antibiotics and cationic antimicrobial peptides. ArnC, an integral membrane glycosyltransferase, attaches a formylated form lipid undecaprenyl phosphate, enabling its association bacterial inner membrane. Here, we present cryo-electron microscopy structures ArnC from S. enterica in apo nucleotide-bound conformations. These reveal conformational transition that...
Controlled greenhouse studies have shown the numerous ways that soil microbes can impact plant growth and development. However, natural communities are highly complex, plants interact with many bacterial fungal taxa simultaneously. Due to logistical challenges associated manipulating more complex microbiome communities, how microbial emergent patterns of therefore remains poorly understood. For instance, do interactions between bacteria fungi generally yield additive (i.e. sum their parts)...
To determine whether glucagon receptor (GCGR) actions are modulated by cellular cholesterol levels.
Patched1 (PTCH1) is a tumor suppressor protein of the mammalian Hedgehog (HH) signaling pathway, implicated in embryogenesis and tissue homeostasis. PTCH1 inhibits G protein–coupled receptor Smoothened (SMO) via debated mechanism involving modulating ciliary cholesterol accessibility. Using extensive molecular dynamics simulations free energy calculations to evaluate transport through PTCH1, we find an energetic barrier ~15 20 kilojoule per mole for export. In silico data are coupled vivo...
Membrane-bound O-acyltransferases (MBOATs) are membrane-embedded enzymes that catalyze acyl chain transfer to a diverse group of substrates, including lipids, small molecules, and proteins. MBOATs share conserved structural core, despite wide-ranging functional specificity across both prokaryotes eukaryotes. The basis catalytic specificity, regulation interactions with the surrounding environment remain uncertain. Here, we combine comparative molecular dynamics (MD) simulations...
Abstract Super-resolved cryogenic correlative light and electron microscopy is a powerful approach which combines the single-molecule specificity sensitivity of fluorescence imaging with nano-scale resolution tomography. Key to this method active control over emissive state fluorescent labels ensure sufficient sparsity localize individual emitters. Recent work has identified proteins (FPs) photoactivate or photoswitch efficiently at temperatures, but long on-times due reduced quantum yield...
ABSTRACT Lipids play important modulatory and structural roles for membrane proteins. Molecular dynamics simulations are frequently used to provide insights into the nature of these proteinlipid interactions. Systematic comparative analysis requires tools that algorithms objective assessment such We introduce PyLipID, a python package identification characterization specific lipid interactions binding sites on proteins from molecular simulations. PyLipID uses community approach site...
Abstract Integral membrane proteins are localised and/or regulated by lipids present in the surrounding bilayer. Whilst bacteria such as E. coli have relatively simple membranes when compared to eukaryotic cells, there is ample evidence that many bacterial bind specific lipids, especially anionic lipid cardiolipin. Here, we apply molecular dynamics simulations assess binding 42 different inner proteins. Our data reveals a strong asymmetry between leaflets, with marked increase of leaflet...
Abstract Interpretation of lipid and lipid-like densities surrounding membrane protein structures solved by cryo-electron microscopy (cryo-EM) is challenging. We developed the LipIDens pipeline for assisted structural interpretation using molecular dynamics (MD) simulations. This protocol details how to establish coarse-grained (CG) simulations proteins in biomimetic membranes, test interaction cut-offs, calculate interactions binding sites, assess quality derived kinetics, compare poses...