Increasing the Affinity of an O-Antigen Polysaccharide Binding Site in Shigella Flexneri Bacteriophage Sf6 Tailspike Protein

10.26434/chemrxiv.11410125 ◽

2019 ◽

Author(s):

R. Sonja Kunstmann ◽

Olof Engström ◽

Marko Wehle ◽

Göran Widmalm ◽

Mark Santer ◽

...

Keyword(s):

Molecular Dynamics ◽

Surface Plasmon Resonance ◽

Binding Site ◽

Shigella Flexneri ◽

Md Simulations ◽

Conformational Space ◽

Binding Affinities ◽

The Impact ◽

Tailspike Protein ◽

Good Agreement

We analysed the tailspike from bacteriophage Sf6 in complex with the O-polysaccharide of the pathogen Shigella flexneri. The conformational space populated by the polyrhamnose backbone of the S. flexneri O-polysaccharide as studied by an octasaccharide in complex with Sf6TSP could be well described with 2D 1H,1H-trNOESY NMR, utilizing a combination of methine-methine and methine-methyl correlations. The results are in good agreement with the conformations obtained from molecular dynamics (MD) simulations. To examine the impact of amino acid exchanges in the glycan binding site of Sf6TSP, MD simulations were used to predict increased O-polysaccharide binding affinities. We used surface plasmon resonance on S. flexneri O-polysaccharide surfaces to measure affinity increases in the obtained mutants. <br>

On the Use of the Discrete Constant pH Molecular Dynamics to Describe the Conformational Space of Peptides

Polymers ◽

10.3390/polym13010099 ◽

2020 ◽

Vol 13 (1) ◽

pp. 99

Author(s):

Cristian Privat ◽

Sergio Madurga ◽

Francesc Mas ◽

Jaime Rubio-Martínez

Keyword(s):

Molecular Dynamics ◽

Amino Acids ◽

Md Simulations ◽

Point Of View ◽

Conformational Space ◽

Conformational Sampling ◽

Protonation State ◽

Constant Ph ◽

Biochemical Systems ◽

Constant Ph Molecular Dynamics

Solvent pH is an important property that defines the protonation state of the amino acids and, therefore, modulates the interactions and the conformational space of the biochemical systems. Generally, this thermodynamic variable is poorly considered in Molecular Dynamics (MD) simulations. Fortunately, this lack has been overcome by means of the Constant pH Molecular Dynamics (CPHMD) methods in the recent decades. Several studies have reported promising results from these approaches that include pH in simulations but focus on the prediction of the effective pKa of the amino acids. In this work, we want to shed some light on the CPHMD method and its implementation in the AMBER suitcase from a conformational point of view. To achieve this goal, we performed CPHMD and conventional MD (CMD) simulations of six protonatable amino acids in a blocked tripeptide structure to compare the conformational sampling and energy distributions of both methods. The results reveal strengths and weaknesses of the CPHMD method in the implementation of AMBER18 version. The change of the protonation state according to the chemical environment is presumably an improvement in the accuracy of the simulations. However, the simulations of the deprotonated forms are not consistent, which is related to an inaccurate assignment of the partial charges of the backbone atoms in the CPHMD residues. Therefore, we recommend the CPHMD methods of AMBER program but pointing out the need to compare structural properties with experimental data to bring reliability to the conformational sampling of the simulations.

High-resolution mining of the SARS-CoV-2 main protease conformational space: supercomputer-driven unsupervised adaptive sampling

Chemical Science ◽

10.1039/d1sc00145k ◽

2021 ◽

Author(s):

Théo Jaffrelot Inizan ◽

Frédéric Célerse ◽

Olivier Adjoua ◽

Dina El Ahdab ◽

Luc-Henri Jolly ◽

...

Keyword(s):

Molecular Dynamics ◽

High Resolution ◽

Adaptive Sampling ◽

Force Fields ◽

Sampling Strategy ◽

Md Simulations ◽

Conformational Space ◽

Many Body ◽

Polarizable Force Fields ◽

Main Protease

We provide an unsupervised adaptive sampling strategy capable of producing μs-timescale molecular dynamics (MD) simulations of large biosystems using many-body polarizable force fields (PFFs).

Structural Properties of G,T-Parallel Duplexes

Journal of Nucleic Acids ◽

10.4061/2010/763658 ◽

2010 ◽

Vol 2010 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Anna Aviñó ◽

Elena Cubero ◽

Raimundo Gargallo ◽

Carlos González ◽

Modesto Orozco ◽

...

Keyword(s):

Molecular Dynamics ◽

Structural Properties ◽

Theoretical Calculations ◽

Md Simulations ◽

Theoretical Studies ◽

Duplex Structure ◽

Strong Stabilization ◽

The Stability ◽

The Impact

The structure of G,T-parallel-stranded duplexes of DNA carrying similar amounts of adenine and guanine residues is studied by means of molecular dynamics (MD) simulations and UV- and CD spectroscopies. In addition the impact of the substitution of adenine by 8-aminoadenine and guanine by 8-aminoguanine is analyzed. The presence of 8-aminoadenine and 8-aminoguanine stabilizes the parallel duplex structure. Binding of these oligonucleotides to their target polypyrimidine sequences to form the corresponding G,T-parallel triplex was not observed. Instead, when unmodified parallel-stranded duplexes were mixed with their polypyrimidine target, an interstrand Watson-Crick duplex was formed. As predicted by theoretical calculations parallel-stranded duplexes carrying 8-aminopurines did not bind to their target. The preference for the parallel-duplex over the Watson-Crick antiparallel duplex is attributed to the strong stabilization of the parallel duplex produced by the 8-aminopurines. Theoretical studies show that the isomorphism of the triads is crucial for the stability of the parallel triplex.

Molecular Dynamics Modellization and Simulation of Water Diffusion through Plant Cutin

Zeitschrift für Naturforschung C ◽

10.1515/znc-1999-1107 ◽

1999 ◽

Vol 54 (11) ◽

pp. 896-902 ◽

Cited By ~ 5

Author(s):

Antonio Matas ◽

Antonio Heredia

Keyword(s):

Experimental Data ◽

Molecular Dynamics ◽

Structural Information ◽

Md Simulations ◽

Water Molecules ◽

Plant Cuticle ◽

X Ray Diffraction ◽

Cross Link ◽

X Ray ◽

Good Agreement

Abstract A theoretical molecular modelling study has been conducted for cutin, the biopolyester that forms the main structural component of the plant cuticle. Molecular dynamics (MD) simulations, extended over several ten picoseconds, suggests that cutin is a moderately flexible netting with motional constraints mainly located at the cross-link sites of functional ester groups. This study also gives structural information essentially in accordance with previously reported experimental data, obtained from X -ray diffraction and nuclear magnetic resonance experiments. MD calculations were also performed to simulate the diffusion of water molecules through the cutin biopolymer. The theoretical analysis gives evidence that water permeation proceedes by a “hopping mechanism”. Coefficients for the diffusion of the water molecules in cutin were obtained from their mean-square displacements yielding values in good agreement with experimental data.

Understanding the Pyrimethamine Drug Resistance Mechanism via Combined Molecular Dynamics and Dynamic Residue Network Analysis

Molecules ◽

10.3390/molecules25040904 ◽

2020 ◽

Vol 25 (4) ◽

pp. 904 ◽

Cited By ~ 1

Author(s):

Arnold Amusengeri ◽

Rolland Bantar Tata ◽

Özlem Tastan Bishop

Keyword(s):

Molecular Dynamics ◽

Drug Resistance ◽

Network Analysis ◽

Binding Free Energy ◽

Resistance Mechanism ◽

Point Mutations ◽

Md Simulations ◽

Conformational Plasticity ◽

New Perspective ◽

The Impact

In this era of precision medicine, insights into the resistance mechanism of drugs are integral for the development of potent therapeutics. Here, we sought to understand the contribution of four point mutations (N51I, C59R, S108N, and I164L) within the active site of the malaria parasite enzyme dihydrofolate reductase (DHFR) towards the resistance of the antimalarial drug pyrimethamine. Homology modeling was used to obtain full-length models of wild type (WT) and mutant DHFR. Molecular docking was employed to dock pyrimethamine onto the generated structures. Subsequent all-atom molecular dynamics (MD) simulations and binding free-energy computations highlighted that pyrimethamine’s stability and affinity inversely relates to the number of mutations within its binding site and, hence, resistance severity. Generally, mutations led to reduced binding affinity to pyrimethamine and increased conformational plasticity of DHFR. Next, dynamic residue network analysis (DRN) was applied to determine the impact of mutations and pyrimethamine binding on communication dispositions of DHFR residues. DRN revealed residues with distinctive communication profiles, distinguishing WT from drug-resistant mutants as well as pyrimethamine-bound from pyrimethamine-free models. Our results provide a new perspective on the understanding of mutation-induced drug resistance.

Molecular Dynamics Study Of Surface Morphological Evolution By Cluster Impacts

MRS Proceedings ◽

10.1557/proc-792-r4.7 ◽

2003 ◽

Vol 792 ◽

Author(s):

Takaaki Aoki ◽

Jiro Matsuo ◽

Isao Yamada

Keyword(s):

Molecular Dynamics ◽

Ion Irradiation ◽

Morphological Evolution ◽

Md Simulations ◽

Impact Area ◽

Cluster Ion ◽

Dynamics Simulations ◽

Large Clusters ◽

The Hill ◽

The Impact

ABSTRACTIn order to understand the characteristics of surface modification process with cluster ion irradiation, molecular dynamics simulations of Ar cluster impacting on Si surface with various surface structures were carried out. It was found that the surface morphology is dynamically deformed with only one cluster impact and the impact process of cluster is different depending on the local surface structure. For example, when an Ar2000 cluster accelerated with 20keV impacted on the convex point of the surface, the hill was compressed and the impact area was smoothed. At the impact on a concave point, a deeper crater was formed compared with the impact on a flat surface. On the other hand, the MD simulations of sequential impacts of large clusters were performed. It was found that the small tip structures on the surface could be removed easily with cluster irradiation. It was shown that surface roughness converges to 15∼20Å and this value agrees with the result obtained by single impact of cluster.

Molecular Dynamics Simulations of Cluster-size Effect on Sputtering Process with Reactive Gas Cluster Ions

MRS Proceedings ◽

10.1557/proc-0908-oo05-07 ◽

2005 ◽

Vol 908 ◽

Author(s):

Takaaki Aoki ◽

Jiro Matsuo

Keyword(s):

Molecular Dynamics ◽

Size Effect ◽

Cluster Size ◽

Incident Energy ◽

Md Simulations ◽

Cluster Ions ◽

Experimental Conditions ◽

Near Surface ◽

The Impact ◽

Reactive Cluster

AbstractTo investigate the size-effect of reactive clusters on sputtering processes, we performed molecular dynamics (MD) simulations of reactive cluster ions with various sizes impacting on solid targets. Various sizes of fluorine clusters, (F2)30, (F2)300 and (F2)3000, were irradiated on a Si(100) target at the same total incident energy of 6 keV. These clusters were irradiated on the same target one after another in order to reproduce real experimental conditions such as the accumulation of fluorine atoms in the target. The MD simulations of sequential cluster impacts enabled to perform various statistical analyses regarding the sputtered particles. The study of cluster size distributions showed that the sputtering process by reactive cluster ion impact has similarity with the emission from quasi-liquid materials excited to hyper-thermal conditions by ion bombardment. However, the major sputtered particles were different with each other; Si for (F2)30 (100 eV/atom), SiF2 for (F2)300 (10 eV/atom), and SiF3 for (F2)3000 (1 eV/atom). At the impact of a large size cluster with low incident energy, a large number of Si-F bondings were generated at the cluster-target interface surface, which enhances formation of volatile SiFx compounds with many fluorine atoms. In contrast, a small cluster with high kinetic energy-per-atom could cause the formation of numerous energetic surface atoms at the near surface region, which could be sputtered without being well fluoridated.

Characterizing Moisture Uptake and Plasticization Effects of Water on Amorphous Amylose Starch Models Using Molecular Dynamics Methods

10.26434/chemrxiv.12582272.v3 ◽

2020 ◽

Author(s):

Jeffrey Sanders ◽

Mayank Misra ◽

Thomas JL Mustard ◽

David J. Giesen ◽

Teng Zhang ◽

...

Keyword(s):

Molecular Dynamics ◽

Moisture Content ◽

Force Field ◽

Moisture Sorption ◽

Md Simulations ◽

A Value ◽

Moisture Sorption Isotherm ◽

Molecular Dynamics Methods ◽

Grand Canonical ◽

Good Agreement

<p>Dynamics and thermophysical properties of amorphous starch were explored using molecular dynamics (MD) simulations. Using the OPLS3e force field, simulations of short amylose chains in water were performed to determine force field accuracy. Using well-tempered metadynamics, a free energy map of the two glycosidic angles of an amylose molecule was constructed and compared with other modern force fields. Good agreement of torsional sampling for both solvated and amorphous amylose starch models was observed. Using combined grand canonical Monte Carlo (GCMC)/MD simulations, a moisture sorption isotherm curve is predicted along with temperature dependence. Concentration-dependent activation energies for water transport agree quantitatively with previous experiments. Finally, the plasticization effect of moisture content on amorphous starch was investigated. Predicted glass transition temperature (Tg) depression as a function of moisture content is in line with experimental trends. Further, our calculations provide a value for the dry Tg for amorphous starch, a value which no experimental value is available.</p><div><br></div>

Insights into the substrate binding mechanism of SULT1A1 through molecular dynamics with excited normal modes simulations

Scientific Reports ◽

10.1038/s41598-021-92480-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Balint Dudas ◽

Daniel Toth ◽

David Perahia ◽

Arnaud B. Nicot ◽

Erika Balog ◽

...

Keyword(s):

Molecular Dynamics ◽

Conformational Changes ◽

Molecular Mechanisms ◽

Normal Modes ◽

Md Simulations ◽

Conformational Space ◽

Metabolizing Enzymes ◽

Protein Ligand Interactions ◽

Ligand Interactions ◽

Excited Normal Modes

AbstractSulfotransferases (SULTs) are phase II drug-metabolizing enzymes catalyzing the sulfoconjugation from the co-factor 3′-phosphoadenosine 5′-phosphosulfate (PAPS) to a substrate. It has been previously suggested that a considerable shift of SULT structure caused by PAPS binding could control the capability of SULT to bind large substrates. We employed molecular dynamics (MD) simulations and the recently developed approach of MD with excited normal modes (MDeNM) to elucidate molecular mechanisms guiding the recognition of diverse substrates and inhibitors by SULT1A1. MDeNM allowed exploring an extended conformational space of PAPS-bound SULT1A1, which has not been achieved up to now by using classical MD. The generated ensembles combined with docking of 132 SULT1A1 ligands shed new light on substrate and inhibitor binding mechanisms. Unexpectedly, our simulations and analyses on binding of the substrates estradiol and fulvestrant demonstrated that large conformational changes of the PAPS-bound SULT1A1 could occur independently of the co-factor movements that could be sufficient to accommodate large substrates as fulvestrant. Such structural displacements detected by the MDeNM simulations in the presence of the co-factor suggest that a wider range of drugs could be recognized by PAPS-bound SULT1A1 and highlight the utility of including MDeNM in protein–ligand interactions studies where major rearrangements are expected.