A5110621507- Advanced Chemical Physics Studies
- Protein Structure and Dynamics
- Receptor Mechanisms and Signaling
- Cannabis and Cannabinoid Research
- Neuroscience and Neuropharmacology Research
- SARS-CoV-2 and COVID-19 Research
- Laser-Matter Interactions and Applications
- Atomic and Molecular Physics
- Mass Spectrometry Techniques and Applications
- Spectroscopy and Quantum Chemical Studies
- Lipid Membrane Structure and Behavior
- Bacteriophages and microbial interactions
- Computational Drug Discovery Methods
- Pancreatic function and diabetes
- Photochemistry and Electron Transfer Studies
- Spectroscopy and Laser Applications
- Pharmacological Receptor Mechanisms and Effects
- High-pressure geophysics and materials
- Quantum, superfluid, helium dynamics
- Diet, Metabolism, and Disease
- Inorganic Fluorides and Related Compounds
- Neuropeptides and Animal Physiology
- Photoreceptor and optogenetics research
- Protein Kinase Regulation and GTPase Signaling
- RNA and protein synthesis mechanisms
Georgia Institute of Technology
2020-2025
University of British Columbia
2025
University of North Carolina at Greensboro
2012-2023
University of Illinois Urbana-Champaign
2020-2021
University of Tennessee at Knoxville
2020-2021
Oak Ridge National Laboratory
2020-2021
Istituto Nanoscienze
2020-2021
AID Atlanta
2021
Greensboro College
2011-2020
Freedom to Live
2015
Counteracting Cannabis What is the role of steroid hormones in vulnerability to addiction? Working with rodents, Vallée et al. (p. 94 ) found that all major drugs abuse (morphine, cocaine, alcohol, nicotine) increase neurosteroid levels, active ingredient cannabis (THC) inducing a particularly large increase. THC and other increased levels pregnenolone, long thought be an inactive precursor downstream steroids. Pregnenolone antagonized most known behavioral somatic effects THC.
Recent isothiocyanate covalent labeling studies have suggested that a classical cannabinoid, (-)-7'-isothiocyanato-11-hydroxy-1',1'dimethylheptyl-hexahydrocannabinol (AM841), enters the cannabinoid CB2 receptor via lipid bilayer (Pei, Y., Mercier, R. W., Anday, J. K., Thakur, G. A., Zvonok, A. M., Hurst, D., Reggio, P. H., Janero, D. R., and Makriyannis, (2008) Chem. Biol. 15, 1207-1219). However, sequence of steps involved in such pathway entry has not yet been elucidated. Here, we test...
The cannabinoid CB(1) receptor transmembrane helix (TMH) 3-4-5-6 region includes an aromatic microdomain comprised of residues F3.25, F3.36, W4.64, Y5.39, W5.43, and W6.48. In previous work, we have demonstrated that aromaticity at position 5.39 in is crucial for proper function CB(1). Modeling studies reported here suggest the inactive state CB(1), binding site inverse agonist/antagonist SR141716A within TMH3-4-5-6 involves direct stacking interactions with as well hydrogen bonding K3.28....
The time step of atomistic molecular dynamics (MD) simulations is determined by the fastest motions in system and typically limited to 2 fs. An increasingly popular approach increase mass hydrogen atoms ∼3 amu decrease parent atom an equivalent amount. This approach, known as hydrogen-mass repartitioning (HMR), permits steps up 4 fs with reasonable simulation stability. While HMR has been applied many published studies date, it not extensively tested for membrane-containing systems. Here, we...
Abstract The trimeric spike (S) glycoprotein, which protrudes from the SARS-CoV-2 viral envelope, binds to human ACE2, initiated by at least one protomer’s receptor binding domain (RBD) switching a "down” (closed) an "up” (open) state. Here, we used large-scale molecular dynamics simulations and two-dimensional replica exchange umbrella sampling calculations with more than thousand windows aggregate total of 160 μ s simulation investigate this transition without glycans. We find that...
In superior cervical ganglion neurons,<i>N</i>-(piperidiny-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1<i>H</i>-pyrazole-3-carboxamide (SR141716A) competitively antagonizes the Ca<sup>2+</sup> current effect of cannabinoid (CB) agonist (<i>R</i>)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-<i>de</i>]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55212-2), and behaves as an inverse by producing opposite effects when applied alone. contrast, in neurons...
In this study, we tested the hypothesis that a CB(1) TMH3-4-5-6 aromatic microdomain, which includes F3.25(190), F3.36(201), W5.43(280), and W6.48(357), is centrally involved in receptor activation, with F3.36(201)/W6.48(357) interaction key to maintenance of CB(1)-inactive state. We have shown previously when W6.48(357) are individually mutated alanine, significant reduction ligand binding affinity observed presence WIN 55,212-2 SR141716A but not CP55,940 anandamide. work presented here,...
GPR55 is a class A G protein-coupled receptor (GPCR) that has been implicated in inflammatory pain, neuropathic metabolic disorder, bone development, and cancer. Initially deorphanized as cannabinoid receptor, shown to be activated by non-cannabinoid ligands such l-α-lysophosphatidylinositol (LPI). While there growing body of evidence physiological pathophysiological roles for GPR55, the paucity specific antagonists limited its study. In collaboration with Molecular Libraries Probe...
The main protease (M
SARS-CoV and SARS-CoV-2 bind to the human ACE2 receptor in practically identical conformations, although several residues of receptor-binding domain (RBD) differ between them. Herein, we have used molecular dynamics (MD) simulations, machine learning (ML), free-energy perturbation (FEP) calculations elucidate differences binding by two viruses. Although only subtle were observed from initial MD simulations RBD-ACE2 complexes, ML identified individual with most distinctive interactions, many...
Quantum molecular dynamics simulations of pure samples and mixtures isotopic hydrogenic species (H, D, T) yield important structural, dynamical, electronic properties that characterize matter at high compressions (\ensuremath{\rho}\ensuremath{\ge}0.25 g/${\mathrm{cm}}^{3}$) moderate temperatures (3000--60 000 K). mechanical treatments the electrons, contained in periodically replicated reference cells ${\mathit{N}}_{\mathit{a}}$ atoms, by density functional tight-binding methods determine...
The rotational branching ratios resulting from (1+1) resonant-enhanced multiphoton ionization of NO via the $A^{2}\ensuremath{\Sigma}^{+}$ Rydberg state are analyzed. Theoretical results using ab initio molecular parameters agree reasonably well with recent experimental data. More importantly, analysis underscores importance nature problem and its complexities. It is shown that, for photoionization a $\ensuremath{\Sigma}$ that leaves ion in state, allowed states satisfy selection rule...
Marijuana is the most widely abused illegal drug, and its spectrum of effects suggests that several receptors are responsible for activity. Two cannabinoid receptor subtypes, CB1 CB2, have been identified, but complex pharmacological properties exogenous cannabinoids endocannabinoids not fully explained by their signaling. The orphan GPR55 binds a subset CB2 ligands has proposed as receptor. This designation, however, controversial result recent studies in which lysophosphatidylinositol...
Adolescence is characterized by drastic behavioral adaptations and comprises a particularly vulnerable period for the emergence of various psychiatric disorders. Growing evidence reveals that pathophysiology these disorders might derive from aberrations normal neurodevelopmental changes in adolescent brain. Understanding molecular underpinnings behavior therefore critical understanding origin psychopathology, but mechanisms trigger are unknown. Here, we hypothesize cannabinoid type-1...
The transient receptor potential subfamily vanilloid type 1 ion channel (TRPV1), located in the peripheral nervous system has been implicated perception of pain and possesses ability to be modulated by various cannabinoid ligands. Because its location, TRPV1 is an ideal target for development novel therapeutics. Literature precedent suggests a wide range ligands can activate TRPV1, but location mode entry not well understood. Understanding modes which cannabinoids enter bind aid rational...
Interfering with the self-assembly of virus nucleocapsids is a promising approach for development novel antiviral agents. Applied to hepatitis B (HBV), this has led several classes capsid assembly modulators (CAMs) that target by either accelerating nucleocapsid or misdirecting it into noncapsid-like particles, thereby inhibiting HBV replication cycle. Here, we have assessed structures early intermediates, bound and without CAMs, using molecular dynamics simulations. We find distinct...
Hepatitis B virus (HBV) is the leading cause of chronic liver pathologies worldwide. HBV nucleocapsid, a key structural component, formed through self-assembly capsid protein units. Therefore, interfering with process promising approach for development novel antiviral agents. Applied to HBV, this has led several classes assembly modulators (CAMs). Here, we report structurally CAMs moderate activity and low toxicity, discovered biophysics-guided combining docking, molecular dynamics...
Abstract An effective approach in the development of novel antivirals is to target assembly viral capsids using capsid modulators (CAMs). CAMs targeting hepatitis B virus (HBV) have two major modes function: they can either accelerate nucleocapsid assembly, retaining its structure, or misdirect it into non-capsid-like particles. Previous molecular dynamics (MD) simulations early capsid-assembly intermediates showed differences protein conformations for apo and bound states. Here, we...