scholarly journals Oxidation state dependent conformational changes of HMGB1 regulates the formation of the CXCL12/HMGB1 heterocomplex

2019 ◽  
Author(s):  
Enrico M. A. Fassi ◽  
Jacopo Sgrignani ◽  
Gianluca D’Agostino ◽  
Valentina Cecchinato ◽  
Maura Garofalo ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Disulfide Bond ◽  
Conformational Changes ◽  
Mammalian Cells ◽  
Redox State ◽  
High Mobility ◽  
Md Simulations ◽  
Conformational Space ◽  
Structure And Dynamics ◽  
State Dependent

AbstractHigh-mobility Group Box 1 (HMGB1) is an abundant protein present in all mammalian cells and involved in several processes. During inflammation or tissue damage, HMGB1 is released in the extracellular space and, depending on its redox state, can form a heterocomplex with CXCL12. The heterocomplex acts exclusively on the chemokine receptor CXCR4 enhancing leukocyte recruitment.Here, we used multi-microsecond molecular dynamics (MD) simulations to elucidate the effect of the disulfide bond on the structure and dynamics of HMGB1.The results of the MD simulations show that the presence or lack of the disulfide bond between Cys23 and Cys45 modulates the conformational space explored by HMGB1, making the reduced protein more suitable to form a complex with CXCL12.

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

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.

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

Polymers ◽  
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.

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

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).

scholarly journals Sorption, Structure and Dynamics of CO2 and Ethane in Silicalite at High Pressure: A Combined Monte Carlo and Molecular Dynamics Simulation Study

Molecules ◽  
2018 ◽  
Vol 24 (1) ◽  
pp. 99 ◽  
Author(s):  
Siddharth Gautam ◽  
Tingting Liu ◽  
David Cole
Keyword(s):  
Molecular Dynamics ◽  
Monte Carlo ◽  
Time Scales ◽  
Rotational Motion ◽  
High Pressures ◽  
Sorption Isotherms ◽  
Md Simulations ◽  
Dynamics Simulation ◽  
Structure And Dynamics ◽  
Low Pressures

Silicalite is an important nanoporous material that finds applications in several industries, including gas separation and catalysis. While the sorption, structure, and dynamics of several molecules confined in the pores of silicalite have been reported, most of these studies have been restricted to low pressures. Here we report a comparative study of sorption, structure, and dynamics of CO2 and ethane in silicalite at high pressures (up to 100 bar) using a combination of Monte Carlo (MC) and molecular dynamics (MD) simulations. The behavior of the two fluids is studied in terms of the simulated sorption isotherms, the positional and orientational distribution of sorbed molecules in silicalite, and their translational diffusion, vibrational spectra, and rotational motion. Both CO2 and ethane are found to exhibit orientational ordering in silicalite pores; however, at high pressures, while CO2 prefers to reside in the channel intersections, ethane molecules reside mostly in the sinusoidal channels. While CO2 exhibits a higher self-diffusion coefficient than ethane at low pressures, at high pressures, it becomes slower than ethane. Both CO2 and ethane exhibit rotational motion at two time scales. At both time scales, the rotational motion of ethane is faster. The differences observed here in the behavior of CO2 and ethane in silicalite pores can be seen as a consequence of an interplay of the kinetic diameter of the two molecules and the quadrupole moment of CO2.

scholarly journals Structure and Dynamics of Glycosphingolipids in Lipid Bilayers: Insights from Molecular Dynamics Simulations

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Ronak Y. Patel ◽  
Petety V. Balaji
Keyword(s):  
Molecular Dynamics ◽  
Lipid Bilayers ◽  
Membrane Structure ◽  
Lipid Membrane ◽  
Biological Membranes ◽  
Md Simulations ◽  
Atomic Level ◽  
Structure And Dynamics ◽  
Hydrogen Bonding Interactions ◽  
Dynamics Simulations

Glycolipids are important constituents of biological membranes, and understanding their structure and dynamics in lipid bilayers provides insights into their physiological and pathological roles. Experimental techniques have provided details into their behavior at model and biological membranes; however, computer simulations are needed to gain atomic level insights. This paper summarizes the insights obtained from MD simulations into the conformational and orientational dynamics of glycosphingolipids and their exposure, hydration, and hydrogen-bonding interactions in membrane environment. The organization of glycosphingolipids in raft-like membranes and their modulation of lipid membrane structure are also reviewed.

Force field development and simulations of senior dialkyl sulfoxides

2016 ◽  
Vol 18 (15) ◽  
pp. 10507-10515 ◽  
Author(s):  
Vitaly V. Chaban
Keyword(s):  
Molecular Dynamics ◽  
Force Field ◽  
Ab Initio ◽  
Md Simulations ◽  
Field Development ◽  
Force Field Development ◽  
Structure And Dynamics ◽  
Ethyl Methyl ◽  
Methyl Sulfoxide ◽  
Diethyl Sulfoxide

Thermodynamics, structure, and dynamics of diethyl sulfoxide (DESO) and ethyl methyl sulfoxide (EMSO) were investigated using ab initio calculations and non-polarizable potential based molecular dynamics (MD) simulations.

scholarly journals Glycan synthesis, structure, and dynamics: A selection

2013 ◽  
Vol 85 (9) ◽  
pp. 1759-1770 ◽  
Author(s):  
Robert Pendrill ◽  
K. Hanna M. Jonsson ◽  
Göran Widmalm
Keyword(s):  
Structural Information ◽  
3D Structure ◽  
Molecular Simulations ◽  
Md Simulations ◽  
Conformational Space ◽  
Torsion Angles ◽  
Structure And Dynamics ◽  
Novel Approach ◽  
Acetyl Group ◽  
Experimental Spectroscopy

Glycan structural information is a prerequisite for elucidation of carbohydrate function in biological systems. To this end we employ a tripod approach for investigation of carbohydrate 3D structure and dynamics based on organic synthesis; different experimental spectroscopy techniques, NMR being of prime importance; and molecular simulations using, in particular, molecular dynamics (MD) simulations. The synthesis of oligosaccharides in the form of glucosyl fluorides is described, and their use as substrates for the Lam16A E115S glucosyl synthase is exemplified as well as a conformational analysis of a cyclic β-(1→3)-heptaglucan based on molecular simulations. The flexibility of the N-acetyl group of aminosugars is by MD simulations indicated to function as a gatekeeper for transitions of glycosidic torsion angles to other regions of conformational space. A novel approach to visualize glycoprotein (GP) structures is presented in which the protein is shown by, for example, ribbons, but instead of stick or space-filling models for the carbohydrate portion it is visualized by the colored geometrical figures known as CFG representation in a 3D way, which we denote 3D-CFG, thereby effectively highlighting the sugar residues of the glycan part of the GP and the position(s) on the protein.

scholarly journals A Virtual Reality Ensemble Molecular Dynamics Workflow to Study Complex Conformational Changes in Proteins

2020 ◽  
Author(s):  
Jordi Juárez-Jiménez ◽  
Philip Tew ◽  
Michael o'connor ◽  
Salome Llabres ◽  
Rebecca Sage ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Virtual Reality ◽  
Conformational Changes ◽  
Large Scale ◽  
A Priori ◽  
Computational Cost ◽  
Md Simulations ◽  
Collective Variables ◽  
Sampling Protocols ◽  
State Models

<p>Molecular dynamics (MD) simulations are increasingly used to elucidate relationships between protein structure, dynamics and their biological function. Currently it is extremely challenging to perform MD simulations of large-scale structural rearrangements in proteins that occur on millisecond timescales or beyond, as this requires very significant computational resources, or the use of cumbersome ‘collective variable’ enhanced sampling protocols. Here we describe a framework that combines ensemble MD simulations and virtual-reality visualization (eMD-VR) to enable users to interactively generate realistic descriptions of large amplitude, millisecond timescale protein conformational changes in proteins. Detailed tests demonstrate that eMD-VR substantially decreases the computational cost of folding simulations of a WW domain, without the need to define collective variables <i>a priori</i>. We further show that eMD-VR generated pathways can be combined with Markov State Models to describe the thermodynamics and kinetics of large-scale loop motions in the enzyme cyclophilin A. Our results suggest eMD-VR is a powerful tool for exploring protein energy landscapes in bioengineering efforts. </p>

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.

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