scholarly journals Cryo-EM Structure and Molecular Dynamics Analysis of the Fluoroquinolone Resistant Mutant of the AcrB Transporter from Salmonella

2020 ◽  
Vol 8 (6) ◽  
pp. 943 ◽  
Author(s):  
Rachel M. Johnson ◽  
Chiara Fais ◽  
Mayuriben Parmar ◽  
Harish Cheruvara ◽  
Robert L. Marshall ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Clinical Importance ◽  
Resistant Mutant ◽  
Md Simulations ◽  
Drug Efflux ◽  
E Coli ◽  
Novel Structure ◽  
Experimental Structure ◽  
Insight Into

Salmonella is an important genus of Gram-negative pathogens, treatment of which has become problematic due to increases in antimicrobial resistance. This is partly attributable to the overexpression of tripartite efflux pumps, particularly the constitutively expressed AcrAB-TolC. Despite its clinical importance, the structure of the Salmonella AcrB transporter remained unknown to-date, with much of our structural understanding coming from the Escherichia coli orthologue. Here, by taking advantage of the styrene maleic acid (SMA) technology to isolate membrane proteins with closely associated lipids, we report the very first experimental structure of Salmonella AcrB transporter. Furthermore, this novel structure provides additional insight into mechanisms of drug efflux as it bears the mutation (G288D), originating from a clinical isolate of Salmonella Typhimurium presenting an increased resistance to fluoroquinolones. Experimental data are complemented by state-of-the-art molecular dynamics (MD) simulations on both the wild type and G288D variant of Salmonella AcrB. Together, these reveal several important differences with respect to the E. coli protein, providing insights into the role of the G288D mutation in increasing drug efflux and extending our understanding of the mechanisms underlying antibiotic resistance.

AN ANALYSIS OF THE THZ FREQUENCY SIGNATURES IN THE CELLULAR COMPONENTS OF BIOLOGICAL AGENTS

2007 ◽  
Vol 17 (02) ◽  
pp. 225-237 ◽  
Author(s):  
ALEXEI BYKHOVSKI ◽  
TATIANA GLOBUS ◽  
TATYANA KHROMOVA ◽  
BORIS GELMONT ◽  
DWIGHT WOOLARD
Keyword(s):  
Molecular Structure ◽  
Structural Similarity ◽  
Md Simulations ◽  
Detection Capability ◽  
Dna Structures ◽  
E Coli ◽  
Cellular Components ◽  
First Time ◽  
Insight Into ◽  
Specific Contribution

The development of an effective biological (bio) agent detection capability based upon terahertz (THz) frequency absorption spectra will require insight into how the constituent cellular components contribute to the overall THz signature. In this work, the specific contribution of ribonucleic acid (RNA) to THz spectra is analyzed in detail. Previously, it has only been possible to simulate partial fragments of the RNA (or DNA) structures due to the excessive computational demands. For the first time, the molecular structure of the entire transfer RNA (tRNA) molecule of E. coli was simulated and the associated THz signature was derived theoretically. The tRNA that binds amino acid tyrosine (tRNAtyr) was studied. Here, the molecular structure was optimized using the potential energy minimization and molecular dynamical (MD) simulations. Solvation effects (water molecules) were also included explicitly in the MD simulations. To verify that realistic molecular signatures were simulated, a parallel experimental study of tRNAs of E. coli was also conducted. Two very similar molecules, valine and tyrosine tRNA were investigated experimentally. Samples were prepared in the form of water solutions with the concentrations in the range 0.01-1 mg/ml. A strong correlation of the measured THz signatures associated with valine tRNA and tyrosine tRNA was observed. These findings are consistent with the structural similarity of the two tRNAs. The calculated THz signature of the tyrosine tRNA of E. coli reproduces many features of our measured spectra, and, therefore, provides valuable new insights into bio-agent detection.

scholarly journals Insight into the Role of Water on the Methylation of Hexamethylbenzene in H‐SAPO‐34 from First Principle Molecular Dynamics Simulations

ChemCatChem ◽  
2019 ◽  
Vol 11 (16) ◽  
pp. 3993-4010 ◽  
Author(s):  
Simon Bailleul ◽  
Sven M. J. Rogge ◽  
Louis Vanduyfhuys ◽  
Veronique Van Speybroeck
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
First Principle ◽  
Dynamics Simulations ◽  
Insight Into

scholarly journals Simulating Absorption Spectra of Flavonoids in Aqueous Solution: A Polarizable QM/MM Study

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 5853
Author(s):  
Sulejman Skoko ◽  
Matteo Ambrosetti ◽  
Tommaso Giovannini ◽  
Chiara Cappelli
Keyword(s):  
Molecular Dynamics ◽  
Aqueous Solution ◽  
Hydrogen Bonding ◽  
Force Field ◽  
Absorption Spectra ◽  
Computational Study ◽  
Md Simulations ◽  
Quantum Mechanical ◽  
Hydrogen Bonding Interactions

We present a detailed computational study of the UV/Vis spectra of four relevant flavonoids in aqueous solution, namely luteolin, kaempferol, quercetin, and myricetin. The absorption spectra are simulated by exploiting a fully polarizable quantum mechanical (QM)/molecular mechanics (MM) model, based on the fluctuating charge (FQ) force field. Such a model is coupled with configurational sampling obtained by performing classical molecular dynamics (MD) simulations. The calculated QM/FQ spectra are compared with the experiments. We show that an accurate reproduction of the UV/Vis spectra of the selected flavonoids can be obtained by appropriately taking into account the role of configurational sampling, polarization, and hydrogen bonding interactions.

Nanomechanical and Friction Properties of Ultrathin Amorphous Carbon Films Studied by Molecular Dynamics Analysis

2010 ◽  
Author(s):  
N. Wang ◽  
K. Komvopoulos
Keyword(s):  
Molecular Dynamics ◽  
Amorphous Carbon ◽  
Md Simulations ◽  
Carbon Films ◽  
Magnetic Storage ◽  
Disk Drives ◽  
Magnetic Medium ◽  
High Density Magnetic Recording ◽  
Protective Overcoats ◽  
Insight Into

An ultrathin (<4 nm) film of amorphous carbon (a-C) is used in contemporary disk drives to protect the magnetic medium of the hard disk from corrosion and mechanical wear due to intermittent impact of the low-flying magnetic head. Because of increasing demands for much higher magnetic storage densities (i.e., >10 Tbits/in2), the a-C film thickness must be decreased to <2 nm. However, the tribological and mechanical properties of such thin a-C films are not well understood and, moreover, are extremely difficult to determine experimentally. The objective of this study was to obtain insight into the tribological behavior of ultrathin a-C films by performing molecular dynamics (MD) simulations. MD results of the hardness and friction properties of nanometer-thick a-C films are interpreted in terms of the ratio of tetrahedral-to-trigonal carbon atom hybridization. A critical thickness for the effective protection of the magnetic medium by the a-C film is estimated from MD results. The results of this study elucidate the nanomechanical and nanotribological properties of ultrathin a-C films used as protective overcoats in extremely-high-density magnetic recording.

Molecular Dynamics insight into the role of tertiary (foldon) interactions on unfolding in Cytochrome c

2009 ◽  
Vol 475 (1-3) ◽  
pp. 111-115 ◽  
Author(s):  
M.Y. Tsai ◽  
A.N. Morozov ◽  
K.Y. Chu ◽  
S.H. Lin
Keyword(s):  
Molecular Dynamics ◽  
Cytochrome C ◽  
Insight Into

scholarly journals QM/MM Molecular Dynamics Investigation of the Binding of Organic Phosphates to the 100 Diaspore Surface

2020 ◽  
Author(s):  
Prasanth Babu Ganta ◽  
Oliver Kühn ◽  
Ashour Ahmed
Keyword(s):  
Molecular Dynamics ◽  
Food System ◽  
Specific Binding ◽  
Md Simulations ◽  
Mineral Surfaces ◽  
Soil Mineral ◽  
Molecular Systems ◽  
Organic Phosphates ◽  
Surface Plane

<div><div><div><p>The fate of phosphorus (P) in the eco-system is strongly affected by the interaction of phos- phates with soil components and especially reactive soil mineral surfaces. As a consequence, P immobilization could occur which eventually leads to P inefficiency and thus unavailability to plants with strong implications on the global food system. A molecular level understanding of the mechanisms of the P binding to soil mineral surfaces could be a key for the development of novel strategies for more efficient P application. Much experimental work has been done to understand P binding to several reactive and abundant minerals especially goethite (α-FeOOH). On the other hand, atomistic modeling of the P-mineral molecular systems using molecular dynamics (MD) simulations is emerging as a new tool which provides more detailed information regarding the mechanisms, nature, and strength of these binding processes. The present study characterize the binding of the most abundant organic phosphates in forest soils, inositol hexaphosphate (IHP) and glycerolphosphate (GP), to the 100 diaspore (α-AlOOH) surface plane. Here, different molecular models have been introduced to simulate typical situations for the P-binding at the diaspore/water interface. For all models, quantum mechanics/molecular mechanics (QM/MM) based MD simulations have been performed to explore the diaspore–IHP/GP–water interactions. The results provide evidence for the formation of monodentate (M) and bidentate (B) motifs for GP and M and as well as two monodentate (2M) motifs for IHP with the surface. The calculated interaction energies suggest that GP and IHP prefer to form the B and 2M motif, respectively. Moreover, IHP exhibited stronger binding than GP with diaspore and water. Further, the role of water in controlling binding strengths via promoting of specific binding motifs, formation of H-bonds, adsorption and dissociation at the surface, as well as proton transfer processes is demonstrated. Finally, the P-binding at the 100 diaspore surface plane is weaker than that at the 010 plane highlighting the influential role of the coordination number of Al atoms at the top surface of diaspore.</p></div></div></div>

scholarly journals Data for Molecular Dynamics Simulations of Escherichia Coli Cytochrome Bd Oxidase with the Amber Force Field

2021 ◽  
Author(s):  
Surl-Hee Ahn ◽  
Christian Seitz ◽  
Vinicius Cruzeiro ◽  
James McCammon ◽  
Andreas Goetz
Keyword(s):  
Escherichia Coli ◽  
Molecular Dynamics ◽  
Force Field ◽  
Drug Targets ◽  
Food Poisoning ◽  
Md Simulations ◽  
Data Bank ◽  
Low Oxygen ◽  
Amber Force Field ◽  
E Coli

<div> <div> <div> <div> <p>Cytochrome <i>bd</i>-type quinol oxidase is an important metalloenzyme that allows many bacteria to survive in low oxygen conditions. Since bd oxidase is found in many prokaryotes but not in eukaryotes, it has emerged as a promising bacterial drug target. Examples of organisms containing bd oxidases include the <i>Mycobacterium tuberculosis (Mtb)</i> bacterium that causes tuberculosis (TB) in humans, the <i>Vibrio cholerae</i> bacterium that causes cholera, the <i>Pseudomonas aeruginosa</i> bacterium that contributes to antibiotic resistance and sepsis, and the <i>Campylobacter jejuni</i> bacterium that causes food poisoning. <i>Escherichia coli (E. coli)</i> is another organism exhibiting the cytochrome <i>bd</i> oxidase. Since it has the highest sequence identity to <i>Mtb</i> (36 %) and we are ultimately interested in finding drug targets for TB, we have built parameters for the <i>E. coli bd </i>oxidase (Protein Data Bank ID number: 6RKO) that are compatible with the all-atom Amber ff14SB force field for molecular dynamics (MD) simulations. Specifically, we built parameters for the three heme cofactors present in all species of bacterial cytochrome <i>bd</i>-type oxidases (heme b<sub>558</sub>, heme b<sub>595</sub>, and heme d) along with their axial ligands. This data report includes the parameter files that can be used with Amber's LEaP program to generate input files for MD simulations using the Amber software package. We also provide the PDB data files of the initial model both by itself and solvated with TIP3P water molecules and counterions. </p> </div> </div> </div> </div>

scholarly journals Sequence-to-structure dependence of isolated IgG Fc complex biantennary N-glycans: A molecular dynamics study

2018 ◽  
Author(s):  
Aoife M Harbison ◽  
Lorna P Brosnan ◽  
Keith Fenlon ◽  
Elisa Fadda
Keyword(s):  
Molecular Dynamics ◽  
Structural Integrity ◽  
Md Simulations ◽  
Structure And Dynamics ◽  
Differential Recognition ◽  
Dependent Cell ◽  
Function Relationship ◽  
Simulation Time ◽  
Core Fucosylation

AbstractFc glycosylation of human immunoglobulins G (IgGs) is essential for their structural integrity and activity. Interestingly, the specific nature of the Fc glycoforms is known to modulate the IgG effector function. Indeed, while core-fucosylation of IgG Fc-glycans greatly affects the antibody-dependent cell-mediated cytotoxicity (ADCC) function, with obvious repercussions in the design of therapeutic antibodies, sialylation can reverse the antibody inflammatory response, and galactosylation levels have been linked to aging, to the onset of inflammation, and to the predisposition to rheumatoid arthritis. Within the framework of a structure-to-function relationship, we have studied the role of the N-glycan sequence on its intrinsic conformational propensity. Here we report the results of a systematic study, based on extensive molecular dynamics (MD) simulations in excess of 62 µs of cumulative simulation time, on the effect of sequence on the structure and dynamics of increasingly larger, complex biantennary N-glycoforms, i.e. from chitobiose to the larger N-glycan species commonly found in the Fc region of human IgGs. Our results show that while core fucosylation and sialylation do not affect the intrinsic dynamics of the isolated (unbound) N-glycans, galactosylation of the α(1-6) arm shifts dramatically its conformational equilibrium from an outstretched to a folded conformation. These findings are in agreement with and can help rationalize recent experimental evidence showing a differential recognition of positional isomers in glycan array data and also the preference of sialyltransferase for the more reachable, outstretched α(1-3) arm in both isolated and Fc-bound N-glycans.

scholarly journals Liquid-like and rigid-body motions in molecular-dynamics simulations of a crystalline protein

2019 ◽  
Author(s):  
David C. Wych ◽  
James S. Fraser ◽  
David L. Mobley ◽  
Michael E. Wall
Keyword(s):  
Molecular Dynamics ◽  
Rigid Body ◽  
Diffraction Data ◽  
Md Simulations ◽  
X Ray Diffraction ◽  
X Ray ◽  
Atom Pairs ◽  
Collective Motions ◽  
Rigid Body Motions ◽  
Insight Into

AbstractTo gain insight into crystalline protein dynamics, we performed molecular-dynamics (MD) simulations of a periodic 2×2×2 supercell of staphylococcal nuclease. We used the resulting MD trajectories to simulate X-ray diffraction and to study collective motions. The agreement of simulated X-ray diffraction with the data is comparable to previous MD simulation studies. We studied collective motions by analyzing statistically the covariance of alpha-carbon position displacements. The covariance decreases exponentially with the distance between atoms, which is consistent with a liquid-like motions (LLM) model, in which the protein behaves like a soft material. To gain finer insight into the collective motions, we examined the covariance behavior within a protein molecule (intra-protein) and between different protein molecules (inter-protein). The inter-protein atom pairs, which dominate the overall statistics, exhibit LLM behavior; however, the intra-protein pairs exhibit behavior that is consistent with a superposition of LLM and rigid-body motions (RBM). Our results indicate that LLM behavior of global dynamics is present in MD simulations of a protein crystal. They also show that RBM behavior is detectable in the simulations but that it is subsumed by the LLM behavior. Finally the results provide clues about how correlated motions of atom pairs both within and across proteins might manifest in diffraction data. Overall our findings increase our understanding of the connection between molecular motions and diffraction data, and therefore advance efforts to extract information about functionally important motions from crystallography experiments.

scholarly journals Forever Young: Structural Stability of Telomeric Guanine-Quadruplexes in Presence of Oxidative DNA Lesions

2020 ◽  
Author(s):  
Tom Miclot ◽  
Camille Corbier ◽  
Alessio Terenzi ◽  
Cécilia Hognon ◽  
Stéphanie Grandemange ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Dynamics ◽  
Structural Stability ◽  
Md Simulations ◽  
Dna Lesions ◽  
Computational Investigation ◽  
Telomeric Dna ◽  
G Quadruplex ◽  
The Stability

AbstractHuman telomeric DNA (h-Telo), in G-quadruplex (G4) conformation, is characterized by a remarkable structural stability that confers it the capacity to resist to oxidative stress producing one or even clustered 8-oxoguanine lesions. We present a combined experimental/computational investigation, by using circular dichroism in aqueous solutions, cellular immunofluorescence assays and molecular dynamics (MD) simulations, that identifies the crucial role of the stability of G4s to oxidative lesions, related also to their biological role as inhibitors of telomerase, an enzyme overexpressed in most cancers associated to oxidative stress.

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