Grace Brannigan

Grace Brannigan
Rutgers, The State University of New Jersey | Rutgers · Center for Computational and Integrative Biology

PhD

About

101
Publications
6,349
Reads
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1,677
Citations
Additional affiliations
April 2017 - present
Rutgers, The State University of New Jersey
Position
  • Professor (Associate)
September 2011 - April 2017
Rutgers, The State University of New Jersey
Position
  • Professor (Assistant)
August 2009 - August 2011
Temple University
Position
  • Research Assistant Professor
Education
September 2000 - July 2006
September 1996 - May 2000
Reed College
Field of study
  • Physics

Publications

Publications (101)
Article
Full-text available
Persistent, direct interactions between proteins in complex phases and small molecules acting as ligands, including processes taking place in lamellar environments like the membrane or in crowded, non-dilute environments, are critical to action of numerous drugs. Few computational approaches have been developed for making quantitative predictions o...
Article
Reconstituted nicotinic acetylcholine receptors (nAChRs) exhibit significant gain-of-function upon addition of cholesterol to reconstitution mixtures, and cholesterol affects the organization of nAChRs within domain-forming membranes, but whether nAChR partitions to cholesterol-rich liquid-ordered (“raft” or lo) domains or cholesterol-poor liquid-d...
Preprint
Full-text available
GABA(A) receptors are pentameric ligand-gated ion channels playing a critical role in the modulation of neuronal excitability. These inhibitory receptors, gated by γ -aminobutyric acid (GABA), can be potentiated and even directly activated by intravenous and inhalational anesthetics. Intersubunit cavities in the transmembrane domain have been consi...
Article
Full-text available
At the neuromuscular junction (NMJ), the nicotinic acetylcholine receptor (nAChR) self-associates to give rise to rapid muscle movement. While lipid domains have maintained nAChR aggregates in vitro, their specific roles in nAChR clustering are currently unknown. In the present study, we carried out coarse-grained molecular dynamics simulations (CG...
Article
Full-text available
The role of electrostatic interactions and mutations that change charge states in intrinsically disordered proteins (IDPs) is well-established, but many disease-associated mutations in IDPs are charge-neutral. The Val66Met single nucleotide polymorphism (SNP) in precursor brain-derived neurotrophic factor (BDNF) is one of the earliest SNPs to be as...
Preprint
Pentameric ligand-gated ion channels (pLGICs) mediate synaptic transmission and are sensitive to their lipid environment. The mechanism of phospholipid modulation of any pLGIC is not well understood. We demonstrate that the model pLGIC, ELIC (Erwinia ligand-gated ion channel), is positively modulated by the anionic phospholipid, phosphatidylglycero...
Article
Full-text available
Significance Proteins rely on the hydrophobic effect to maintain structure and interactions with the environment. Surprisingly, natural selection on amino acid hydrophobicity has not been detected using modern genetic data. Analyses that treat each amino acid separately do not reveal significant results, which we confirm here. However, because the...
Article
Full-text available
Polyunsaturated fatty acids (PUFAs) inhibit pentameric ligand-gated ion channels (pLGICs) but the mechanism of inhibition is not well understood. The PUFA, docosahexaenoic acid (DHA), inhibits agonist responses of the pLGIC, ELIC, more effectively than palmitic acid, similar to the effects observed in the GABA A receptor and nicotinic acetylcholine...
Preprint
Full-text available
Polyunsaturated fatty acids (PUFAs) inhibit pentameric ligand-gated ion channels (pLGICs) but the mechanism of inhibition is not well understood. The PUFA, docosahexaenoic acid (DHA), inhibits agonist responses of the pLGIC, ELIC, more effectively than palmitic acid, similar to the effects observed in the GABA A receptor and nicotinic acetylcholine...
Preprint
Hydrophobic interactions have long been established as essential to stabilizing structured proteins as well as drivers of aggregation, but the impact of hydrophobicity on the functional significance of sequence variants has rarely been considered in a genome-wide context. Here we test the role of hydrophobicity on functional impact using a set of 7...
Article
Full-text available
Understanding the molecular evolution of the SARS‐CoV‐2 virus as it continues to spread in communities around the globe is important for mitigation and future pandemic preparedness. Three‐dimensional structures of SARS‐CoV‐2 and other coronaviral proteins archived in the Protein Data Bank were used to analyze viral proteome evolution during the fir...
Article
The nicotinic acetylcholine receptor (nAChR) and other pentameric ligand-gated ion channels are native to neuronal membranes with an unusual lipid composition. While it is well-established that these receptors can be significantly modulated by lipids, the underlying mechanisms have been primarily studied in model membranes with few lipid species. H...
Article
Full-text available
Ketamine is an anesthetic, analgesic, and antidepressant whose secondary metabolite (2R,6R)-hydroxynorketamine (HNK) has N-methyl-d-aspartate-receptor-independent antidepressant activity in a rodent model. In humans, naltrexone attenuates its antidepressant effect, consistent with opioid pathway involvement. No detailed biophysical description is a...
Preprint
Full-text available
The nicotinic acetylcholine receptor (nAChR) and other pentameric ligand-gated ion channels (pLGICs) are native to neuronal membranes with an unusual lipid composition. While it is well-established that these receptors can be significantly modulated by lipids, the underlying mechanisms have been primarily studied in model membranes with only a few...
Preprint
Three-dimensional structures of SARS-CoV-2 and other coronaviral proteins archived in the Protein Data Bank were used to analyze viral proteome evolution during the first six months of the COVID-19 pandemic. Analyses of spatial locations, chemical properties, and structural and energetic impacts of the observed amino acid changes in >48,000 viral p...
Article
Full-text available
Phospholipids are key components of cellular membranes and are emerging as important functional regulators of different membrane proteins, including pentameric ligand-gated ion channels (pLGICs). Here, we take advantage of the prokaryote channel ELIC (Erwinia ligand-gated ion channel) as a model to understand the determinants of phospholipid intera...
Article
The voltage-dependent anion channel (VDAC) forms the primary diffusion pore of the outer mitochondrial membrane. In its apo form, VDAC adopts an open conformation with high conductance. States of lower conductance can be induced by ligand binding or the application of voltage. Here, we clarify at the atomic level how β-NADH binding leads to a low-c...
Article
Full-text available
Pentameric ligand-gated ion channels (pLGICs) are essential determinants of synaptic transmission, and are modulated by specific lipids including anionic phospholipids. The exact modulatory effect of anionic phospholipids in pLGICs and the mechanism of this effect are not well understood. Using native mass spectrometry, coarse-grained molecular dyn...
Article
Agonists at the α2 adrenergic receptor produce sedation, increase focus, provide analgesia, and induce centrally-mediated hypotension and bradycardia, yet neither their dynamic interactions with adrenergic receptors nor their modulation of neuronal circuit activity is completely understood. Photoaffinity ligands of α2 adrenergic agonists have the p...
Article
Full-text available
The nicotinic acetylcholine receptor (nAChR) is an excitatory pentameric ligand-gated ion channel (pLGIC), homologous to the inhibitory γ-aminobutyric acid (GABA) type A receptor targeted by pharmaceuticals and endogenous sedatives. Activation of the GABAA receptor by the neurosteroid allopregnanolone can be inhibited competitively by thyroid hormo...
Preprint
Full-text available
Pentameric ligand-gated ion channels (pLGICs) are essential determinants of synaptic transmission, and are modulated by specific lipids including anionic phospholipids. The exact modulatory effect of anionic phospholipids in pLGICs and the mechanism of this effect are not well understood. Using native mass spectrometry, coarse-grained molecular dyn...
Preprint
At the neuromuscular junction (NMJ), the nicotinic acetylcholine receptor (nAChR) self-associates to give rise to rapid muscle movement. While lipid domains have maintained nAChR aggregates in-vitro, their specific roles in nAChR clustering are currently unknown. In the present study, we carried out coarse-grained molecular dynamics simulations (CG...
Preprint
div>The role of electrostatic interactions and mutations that change charge states in intrinsically disordered proteins (IDPs) is well-established, but many disease-associated mutations in IDPs are charge-neutral. The Val66Met single nucleotide polymorphism (SNP) encodes a hydrophobic-to-hydrophobic mutation at the midpoint of the prodomain of prec...
Preprint
Reconstituted nicotinic acetylcholine receptors (nAChR) exhibit significant gain-of-function upon addition of cholesterol to reconstitution mixtures, and experimentally observed clustering of nAChRs within membranes is cholesterol-sensitive, leading to a common expectation that nAChRs will partition into cholesterol-rich liquid ordered ("raft") dom...
Chapter
Efforts to detect binding modes of general anesthetics (GAs) for pentameric ligand-gated ion channels (pLGICs) are often complicated by a large number of indicated sites, as well as the challenges of ranking sites by affinity and determining which sites are occupied at clinical concentrations. Physics-based computational methods offer a powerful ro...
Chapter
Several essential ionotropic neurotransmitter receptors, including the nicotinic acetylcholine receptor (nAChR) and gamma-aminobutyric acid (GABA) type A receptor (GABAAr), belong to the family of pentameric ligand-gated ion channels (pLGICs). Function of these receptors is particularly sensitive to their lipid environment, including cholesterol an...
Article
Full-text available
Propofol, an intravenous anesthetic, is a positive modulator of the GABAA receptor, but the mechanistic details, including the relevant binding sites and alternate targets, remain disputed. Here we undertook an in-depth study of alkylphenol-based anesthetic binding to synaptic membranes. We designed, synthesized and characterized a chemically activ...
Article
Anesthetic photoaffinity ligands have had an increasing presence within anesthesiology research. These ligands mimic parent general anesthetics and allow investigators to study anesthetic interactions with receptors and enzymes; identify novel targets; and determine distribution within biological systems. To date, nearly all general anesthetics use...
Presentation
Full-text available
The Voltage Dependent Anion Channel (VDAC) is a mitochondrial outer membrane protein that mediates transfer of ions and small metabolites. It also allows apoptotic factors like cytochrome C into the cytoplasm, thereby playing a crucial role in mediating programmed cell death (apoptosis). Previous studies have indicated that Nicotinamide adenine din...
Presentation
Type-A γ-aminobutyric acid receptors (GABAARs) are pentameric ligand-gated ion channels that are ubiquitous to the central nervous system (CNS) and critical for regulating neuronal excitability. These inhibitory receptors, gated by γ-aminobutyric acid (GABA), can be potentiated and also directly activated by certain exogenous and endogenous lipophi...
Presentation
Nicotinic acetylcholine receptors (nAChRs) are pentameric Ligand Gated Ion Channels that are critical to signaling across synapses and the neuromuscular junction; such signaling is facilitated by high densities of nAChRs in the post-synaptic membrane. Organization of nAChRs, including partitioning behavior in membranes containing distinct lipid dom...
Article
Full-text available
Structural mechanisms of modulation of γ-aminobutyric acid (GABA) type A receptors by neurosteroids and hormones remain unclear. The thyroid hormone L-3,5,3'-triiodothyronine (T3) inhibits GABAA receptors at micromolar concentrations and has common features with neurosteroids such as allopregnanolone (ALLOP). Here we use functional experiments on α...
Article
The gating of pentameric ligand-gated ion channels is sensitive to a variety of allosteric modulators that act on structures peripheral to those involved in the allosteric pathway leading from the agonist site to the channel gate. One such structure, the lipid-exposed transmembrane α helix, M4, is the target of lipids, neurosteroids, and disease-ca...
Article
Full-text available
Membrane proteins mediate processes that are fundamental for the flourishing of biological cells. Membrane-embedded transporters move ions and larger solutes across membranes; receptors mediate communication between the cell and its environment and membrane-embedded enzymes catalyze chemical reactions. Understanding these mechanisms of action requi...
Article
Full-text available
The discovery of Intrinsically Disordered Proteins (IDP) has challenged the structure-function paradigm and required new approaches for identifying functional mechanisms of proteins. Disease-associated Single Nucleotide Polymorphisms (SNP) are common in the disordered regions of proteins (>21.7 %), but not much is known about their effect on the co...
Article
The gating of pentameric ligand gated ion channels (pLGICs) is sensitive to a variety of allosteric modulators that act on the transmembrane domain, including lipids. Here, we use two prokaryotic homologs, GLIC and ELIC, to examine the role of the lipid-exposed transmembrane a-helix, M4, in the allosteric regulation of pLGICs. Aromatic interactions...
Article
The mitochondrial voltage-dependent anion channel (VDAC) allows passage of ions and metabolites across the mitochondrial outer membrane. Cholesterol binds mammalian VDAC, and we investigated the effects of binding to human VDAC1 with atomistic molecular dynamics simulations that totaled 1.4 μs. We docked cholesterol to specific sites on VDAC that w...
Article
Full-text available
Modulation of the GABA type A receptor (GABAAR) function by cholesterol and other steroids is documented at the functional level, yet its structural basis is largely unknown. Current data on structurally related modulators suggest that cholesterol binds to subunit interfaces between transmembrane domains of the GABAAR. We construct homology models...
Article
Pentameric ligand-gated ion channels (pLGICs) conduct upon the binding of an agonist and are fundamental to neurotransmission. New insights into the complex mechanisms underlying pLGIC gating, ion selectivity and modulation have recently been gained via a series of crystal structures in prokaryotes and Caenorhabditis elegans, as well as computation...
Article
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Article
Full-text available
Disorders of the thyroid cause a multitude of neurological dysfunctions including depression, anxiety, and psychosis. Thyroid hormones have been primarily thought to act via genomic mechanisms throughout the organism; however, recently another mechanism has been proposed for the adult brain. We hypothesize that the thyroid hormone triiodothyronine...
Article
Effects on a human GABA(A) receptor of cholesterol molecules bound to its transmembrane domain are investigated using modeling and explicit, all-atom molecular dynamics simulations. A new homology model of an α1 β1 γ2 GABA(A)R is constructed based on the crystal structure of the glutamate-gated chloride channel of C. elegans. The receptor is simula...
Data
Design of the collective variable restraints. Solid lines: Boltzmann transform of the distribution of the five distances between M2 helices (see Methods) in an unbiased control simulation. Dotted line: flat-bottom restraint potential applied to confine the pore to the open basin. (EPS)
Data
Location of crystallographic DDM detergent and bromo-lidocaine in the GLIC pore. M2 helices of GLIC are shown as grey cylinders (one omitted for clarity), with isoleucine residues 232 and 239 as cyan spacefill. DDM molecules from structure 3EAM [27] are shown as sticks (one omitted for clarity). Bromine atom of bromo-lidocaine from structure 2XQ3 [...
Data
Full-text available
Method for propofol parameterization. (PDF)
Data
Propofol topology file in CHARMM format. (TXT)
Data
Anesthetic binding sites in the unrestrained pore conformation. Left: View of the GLIC channel with two propofol molecules blocking an unrestrained pore (shown in red and orange), and one bound in the crystallographic binding site (purple). Center: Two propofol molecules in the pore formed by M2 helices (gray). Right: Analogous magnification of two...
Data
Propofol parameter file in CHARMM format, including CMAP terms. (TXT)
Data
Root mean square deviations (RMSD) averaged over all C atoms in the protein. Black lines represent the open pore, red lines represent the closed pore, solid lines are for the doubly occupied pore, and dashed lines are for the singly occupied pore. For the closed pore occupied by a single isoflurane, two trajectories have been used. In this case, on...
Data
Root mean square deviations (RMSD) averaged over C atoms in the M2 helices. Black lines represent the open pore, red lines represent the closed pore, solid lines are for the doubly occupied pore, and dashed lines are for the singly occupied pore. For the closed pore occupied by a single isoflurane, two trajectories have been used. In this case, one...