Jeffry D Madura

Duquesne University · The Department of Chemistry and Biochemistry

This abstract was awarded AAI Laboratory Travel Grant

In undergraduate physical chemistry, Schrödinger’s equation is solved for a variety of cases. In doing so, the energies and wave functions of the system can be interpreted to provide connections with the physical system being studied. Solving this equation by hand for a one-dimensional system is a manageable task, but it becomes time-consuming once...

In this technology report, a tool is provided for teaching reciprocal space to undergraduates in physical chemistry and materials science courses. Reciprocal space plays a vital role in understanding a material’s electronic structure and physical properties. Here, we provide an example based on previous work in the Journal of Chemical Education lit...

There is a pressing need for new therapeutics to reactivate covalently inactivated acetylcholinesterase (AChE) due to exposure to organophosphorus (OP) compounds. Current reactivation therapeutics (RTs) are not broad-spectrum and suffer from other liabilities, specifically the inability to cross the blood-brain-barrier. Additionally, the chemical d...

The bacterial leucine transporter (LeuT), a close homologue of the eukaryote monoamine transporters (MATs), currently serves as a powerful template for computer simulations of MATs. Transport of the amino acid leucine through the membrane is made possible by the sodium electrochemical potential. Recent reports indicate that the substrate transport...

Huntington's disease is a member of a group of neurodegenerative diseases called polyglutamine diseases, which are characterized by mutations that cause elongated polyglutamine repeats in proteins. Mutated proteins misfold and aggregate into amyloid-like fibrils in the neuron. Experimental techniques are used to analyze the structure of polyglutami...

Neurotransmitter transporter proteins serve a critical role in the synaptic cleft, aiding in the maintenance of synaptic concentrations of neurotransmitters, terminating neurotransmitter effect via a process known as reuptake. The serotonin transporter (SERT) belongs to the larger monoamine transporter (MAT) family, and is responsible for the reupt...

In order to better understand the allostery at a molecular level, state-dependent crosslinking studies coupled with multidimensional MS were conducted on glycine receptor (GlyR) stabilized in different allosteric states. Predominant allosteric states were stabilized using wild type or mutated receptor in the presence of selected ligands: resting (n...

Previous structure-activity relationship studies indicate that a series of cocaine analogs, 3β-aryltropanes with 2ß-diarylmethoxy substituents, selectively bind to the dopamine transporter (DAT) with nanomolar affinities that are 10-fold greater than the affinities of their corresponding 2α-enantiomers. The present study compared these compounds to...

High-temperature, solid-state synthesis in the Li2MnSnS4 system led to the discovery of two new polymorphic compounds that were analyzed using single crystal X-ray diffraction. The α-polymorph crystallizes in Pna21 with the lithium cobalt (II) silicate, Li2CoSiO4, structure type, where Z=4, R1=0.0349 and wR2=0.0514 for all data. The β-polymorph pos...

Hundreds of millions of U.S. dollars are invested in the research and development of a single drug. Lead compound development is an area ripe for new design strategies. Therapeutic lead candidates have been traditionally found using high-throughput in vitro pharmacological screening, a costly method for assaying thousands of compounds. This approac...

Frontiers in Computational Chemistry, originally published by Bentham and now distributed by Elsevier, presents the latest research findings and methods in the diverse field of computational chemistry, focusing on molecular modeling techniques used in drug discovery and the drug development process. This includes computer-aided molecular design, dr...

Guidelines for submitting commentsPolicy: Comments that contribute to the discussion of the article will be posted within approximately three business days. We do not accept anonymous comments. Please include your email address; the address will not be displayed in the posted comment. Cell Press Editors will screen the comments to ensure that they...

Molecular dynamics simulation provides a powerful and accurate method to model protein conformational change, yet timescale limitations often prevent direct assessment of the kinetic properties of interest. A large number of molecular dynamic steps are necessary for rare events to occur, which allow a system to overcome energy barriers and conforma...

The bacterial leucine transporter LeuT retains significant secondary structure similarities to the human monoamine transporters (MAT) such as the dopamine and serotonin reuptake proteins. The primary method of computational study of the MATs has been through the use of the crystallized LeuT structure. Different conformations of LeuT can give insigh...

Discovery of new inhibitors of the plasmalemmal monoamine transporters (MATs) continues to provide pharmacotherapeutic options for depression, addiction, attention deficit disorders, psychosis, narcolepsy and Parkinson's disease. The recent windfall of high-resolution MAT structural information afforded by x-ray crystallography has enabled the use...

Equilibrium peptide conformations in solution, especially in the presence of salts, has been of interest for several decades. The fundamental interactions that determine the dominant peptide conformations in solution have been experimentally and computationally probed; however, a unified understanding has not yet emerged. In a previous study, we pe...

The zinc metalloprotease neprilysin (NEP) promiscuously degrades small bioactive peptides. NEP is amongst a select group of metalloenzymes that degrade the amyloid beta-peptide (Aβ) in vivo and in situ. Since accumulation of neurotoxic Aβ aggregates in the brain appears to be a causative agent in the pathophysiology of Alzheimer's disease (AD), inc...

Guidelines for submitting commentsPolicy: Comments that contribute to the discussion of the article will be posted within approximately three business days. We do not accept anonymous comments. Please include your email address; the address will not be displayed in the posted comment. Cell Press Editors will screen the comments to ensure that they...

Monoamine transporters are a key feature in controlling interneuron communication by facilitating the reuptake of neurotransmitters such as dopamine, serotonin, and norepinephrine. These reuptake transporters have been computationally studied primarily through the use of homology modeling to the structurally related bacterial LeuT structure or by d...

Huntington's disease is one of nine neurodegenerative diseases characterized by gene mutations causing polyglutamine (polyQ) repeats in various proteins. Mutated proteins misfold, aggregate, and form amyloid-like fibrils in the neuron. As of now, the aggregation mechanism of these polyglutamine proteins is not well understood. Experimental techniqu...

The inactivation of acetylcholinesterase (AChE) by organophosphorus agent (OP) compounds is a serious problem regardless of how the individual was exposed. The reactivation of OP-inactivated AChE is dependent on the OP conjugate, and commonly a specific oxime is better at reactivating a specific OP conjugate than several diverse OP conjugates. The...

Global transitions of proteins, which usually occur on the time scale of microseconds or more, are beyond the capacity of full-atomic conventional molecular dynamics (MD) simulations. Due to this limitations elastic network models, such as the Anisotropic Network Model (ANM), have been widely used to simulate such transitions. However, a direct com...

Transporters of the monoamines serotonin, dopamine, and norepinephrine are plasma membrane proteins belonging to the neurotransmitter sodium symporter¬ family (NSS). Monoamine transporters (MATs) by facilitating reuptake of neurotransmitters from the synapse into the presynaptic nerve terminal, regulate neurotransmitter chemical signaling and maint...

Efficient and accurate mapping of transition pathways is a challenging problem in allosteric proteins. We propose here a to our knowledge new methodology called collective molecular dynamics (coMD). coMD takes advantage of the collective modes of motions encoded by the fold, simultaneously evaluating the interactions and energetics via a full-atomi...

Introduction: In spite of research efforts spanning six decades, the most prominent antidepressant drugs to date still carry several adverse effects, often serious enough to warrant discontinuation of the drug. Molecular mechanisms of depression are now better understood such that some of the specific receptors responsible can be targeted for acti...

One pathological effect of polyglutamine (polyQ) diseases, such as Huntington's disease, is the aggregation of polyQ tracts in nerve cells. These aggregates form larger fibrils in the cells called inclusions. Though the exact pathological role these inclusions play is unknown, an increase in their development is directly correlated to progression o...

Efficient and accurate mapping of transition pathways is a challenging problem in allosteric proteins. We propose here a new methodology which facilitates the sampling of the conformational space by recruiting all modes of motions naturally encoded by the protein architecture, while evaluating the atomic interactions and energetics via full-atomic...

The conformations that proteins adopt in solution are a function of both their primary structure and surrounding aqueous environment. Recent experimental and computational work on small peptides, e.g., polyK, polyE, and polyR, have highlighted an interesting and unusual behavior in the presence of aqueous ions such as ClO(4)(-), Na(+), and K(+). No...

With the breakthrough crystallization of the bacterial leucine transporter protein LeuT, the first available X-ray structure for the neurotransmitter/sodium symporter family, development of 3-D computational models is suddenly essential for structure-function studies on the plasmalemmal monoamine transporters (MATs). LeuT-based MAT models have been...

Monoamine transporters (MATs) function by coupling ion gradients to the transport of dopamine, norepinephrine, or serotonin. Despite their importance in regulating neurotransmission, the exact conformational mechanism by which MATs function remains elusive. To this end, we have performed seven 250 ns accelerated molecular dynamics simulations of th...

The dopamine transporter (DAT) facilitates the regulation of synaptic neurotransmitter levels. As a target for therapeutic and illicit psycho-stimulant drugs like antidepressants and cocaine, DAT has been studied intensively. Despite a wealth of mutational and physiological data regarding DAT, the structure remains unsolved and details of the trans...

Removal of substrate (+)-camphor from the active site of cytochrome P450(cam) (CYP101A1) results in nuclear magnetic resonance-detected perturbations in multiple regions of the enzyme. The (1)H-(15)N correlation map of substrate-free diamagnetic Fe(II) CO-bound CYP101A permits these perturbations to be mapped onto the solution structure of the enzy...

Experimental and computational work has shown that the presence of ions in solution affects the conformations of proteins. The driving force behind the effect of ions on shifts in the conformational equilibria of proteins is not known. We believe that ions modulate a peptide’s hydration, thereby causing it to undergo a conformational shift. We have...

The monoamine transporters (MATs) are a family of neurotransmitter transporters located on the presynapse of a neuron. These monoamine transporters regulate the levels of neurotransmitters available in the synapse to bind to post-synaptic receptors. One of the MATs, the dopamine transporter (DAT) is a target of various therapeutic and illicit drugs...

The study of very large biomolecular systems over extended spatial and temporal scales is being accomplished through the use of coarse-grained (CG) models. The successes of several CG models, including MARTINI and CMM-CG, and their implementation in current molecular dynamics (MD) software are discussed. In addition, we highlight multiscale CG and...

The invention pertains to an active agent, and pharmaceutical composition containing it, which is useful as an antagonist to treat addiction to or dependence on cocaine or other psychostimulant substances of abuse.

The role that alkali cations in non-aqueous solvents play in organic reactions continues to be a topic of interest. In particular it has been observed that these cations can alter the stereoselectivity of organic reactions. Our interest is to first understand the nature of cation–ether complexes, then to investigate the role that the cation plays i...

The serotonin transporter (SERT), a member of the neurotransmitter sodium symporter (NSS) family, is responsible for the reuptake of serotonin from the synaptic cleft to maintain neurotransmitter homeostasis. SERT is established as an important target in the treatment of anxiety and depression. Because a high-resolution crystal structure is not ava...

Ligand virtual screening (VS) using the vestibular binding pocket of a 3-D monoamine transporter (MAT) computational model followed by in vitro pharmacology led to the identification of a human serotonin transporter (hSERT) inhibitor with modest affinity (hSERT K(i) = 284 nM). Structural comparison of this VS-elucidated compound, denoted MI-17, to...

Residual dipolar couplings (RDCs) were used as restraints in fully solvated molecular dynamics simulations of reduced substrate- and carbonmonoxy-bound cytochrome P450(cam) (CYP101A1), a 414-residue soluble monomeric heme-containing camphor monooxygenase from the soil bacterium Pseudomonas putida. The (1)D(NH) residual dipolar couplings used as res...

Alzheimer's disease (AD) is a progressive neurodegenerative disease resulting in cognitive and behavioral impairment. The two classic pathological hallmarks of AD include extraneuronal deposition of amyloid β (Aβ) and intraneuronal formation of neurofibrillary tangles (NFTs). NFTs contain hyperphosphorylated tau. Tau is the major microtubule-associ...

Sodium perchlorate salt (NaClO(4)) is commonly used as an internal intensity standard in ultraviolet resonance Raman (UVRR) spectroscopy experiments. It is well known that NaClO(4) can have profound effects on peptide stability. The impact of NaClO(4) on protein stability in UVRR experiments has not yet been fully investigated. It is well known fro...

Sodium perchlorate salt (NaClO 4) is commonly used as an internal intensity standard in ultraviolet resonance Raman (UVRR) spectroscopy experiments. It is well known that NaClO 4 can have profound effects on peptide stability. The impact of NaClO 4 on protein stability in UVRR experiments has not yet been fully investigated. It is well known from e...

Scitation is the online home of leading journals and conference proceedings from AIP Publishing and AIP Member Societies

Acetylcholinesterase (AChE) plays a crucial role in nerve impulse transmission at cholinergic synapses by rapid hydrolysis of the neurotransmitter acetylcholine (ACh). AChE has become an important drug target because partial inhibition of AChE results in modest increase in ACh levels that can have therapeutic benefits, thus AChE inhibitors have pro...

Recognition of psychostimulants such as cocaine and the amphetamines by the dopamine transporter (DAT) protein is principally responsible for the euphoria and addiction associated with these drugs. Using as a template the crystal structure of a distantly related bacterial leucine transporter, 3-D DAT computer molecular models have been generated. L...

The dopamine transporter (DAT) operates via facilitated diffusion, harnessing an inward Na(+) gradient to drive dopamine from the extracellular synaptic cleft to the neuron interior. The DAT is relevant to central nervous system disorders such as Parkinson disease and attention-deficit hyperactivity disorder and is the primary site of action for th...

We used CD, UV resonance Raman spectroscopy, and molecular dynamics simulation to examine the impact of salts on the conformational equilibria and the Ramachandran Psi angle (un)folding Gibbs free energy landscape coordinate of a mainly polyalanine alpha-helical peptide, AP of sequence AAAAA(AAARA)(3)A. NaClO(4) stabilizes alpha-helical-like confor...

Experimental evidence has been provided for a functionally relevant cis-trans isomerization of the Ile88-Pro89 peptide bond in cytochrome P450(cam) (CYP101). The isomerization is proposed to be a key element of the structural reorganization leading to the catalytically competent form of CYP101 upon binding of the effector protein putidaredoxin (Pdx...

Free energy perturbation Monte Carlo (FEP/MC) simulations are performed for both the liquid and solid phases of water to determine the melting temperature of several popular three and four-site water models. Gibbs free energy vs. temperature plots are constructed from the simulations to determine the melting temperature. For the liquid phase, stand...

The gaseous and solution phase structures of CO2(aq) are investigated to aid in the development of CO2(aq) MM parameters for use in the CO2 sequestration modeling studies. Previous experimental and computational studies indicate two energetic minima for the interaction of a single CO2 and single water molecule, termed the T-structure and H-structur...

We use molecular dynamics simulations to study the water structure and dynamics around the winter flounder antifreeze protein (AFP) and its two mutant forms in which the four key threonine residues of the winter flounder AFP are mutated to alanines and serines, respectively. The TIP4P-Ew water model is used to better describe the water interactions...

Protein dynamics depends on the environment and the inclusion of salts in the simulation of folding/unfolding becomes extremely necessary when comparing energy barriers or reaction rates with experimental results. The aim of this study is to investigate the effects of three sodium salts: NaClO4,NaCl and Na2SO4 on the helical stability of AP, a main...

Salt solutions have been the object of study of many scientists through history, but one of the most important findings came along when the Hofmeister series were discovered. Their importance arises from the fact that they influence the relative solubility of proteins, and solubility is directly related to one of today's holy grails: protein foldin...

The aim of this study is to investigate the significance of nonpolar functional groups in the surface orientation-dependent adsorption of natural and synthetic antifreeze proteins (AFPs) on ice. We investigate using nanoliter osmometry, ice etching, and circular dichroism spectroscopy a series of nine designed α-helical peptides to probe the nature...

Silica dust particles in the form of quartz (but not kaolin) have been hypothesized to promote pulmonary diseases such as silicosis. The hypothesis is that quartz and kaolin have a comparable membranolytic potential on a specific surface area basis, and they have a comparable cytotoxic potential for lavaged pulmonary macrophages. Suppression of the...

Three-dimensional quantitative structure-activity relationship (3D-QSAR) models have been constructed using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) for a series of structurally related steroidal alkaloids as butyrylcholinesterase (BuChE) inhibitors. Docking studies were employe...

Introduction3D-QSAR MethodologynD-QSAR MethodologyVirtual High-Throughput Screening (VHTS)Receptor-Dependent (RD) QSARConclusion

We demonstrate a calculated alpha-helix peptide folding energy landscape which accurately simulates the first experimentally measured alpha-helix melting energy landscape. We examine a 21-amino acid, mainly polyalanine peptide and calculate the free energy along the Psi Ramachandran angle secondary folding coordinate. The experimental free energy l...

Antifreeze proteins (AFPs) protect many plants and organisms from freezing in low temperatures. Of the different AFPs, the most studied AFP Type I from winter flounder is used in the current computational studies to gain molecular insight into its adsorption at the ice/water interface. Employing molecular dynamics simulations, we calculate the free...

Glycosidase and lectins both bind sugars, but only the glycosidases have catalytic activity. The glycosidases occur among over 100 evolved protein families and Family 18 is one of the two chitinases (EC 3, 2.1.14) families. Interestingly, lectins are also in this evolutionary group of Family 18 glycosidase proteins. The proteins belonging to the en...

Pharmacological and behavioral studies indicate that binding of cocaine and the amphetamines by the dopamine transporter (DAT) protein is principally responsible for initiating the euphoria and addiction associated with these drugs. The lack of an X-ray crystal structure for the DAT or any other member of the neurotransmitter:sodium symporter (NSS)...

Non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) have become an inherent component of highly active antiretroviral therapy (HAART) in the treatment of human immunodeficiency virus type 1 (HIV-1) infections. One of the most serious problems associated with NNRTIs is that the virus exhibits resistance to the drug through mutation once th...