scholarly journals The role of the first transmembrane helix in bacterial YidC: Insights from the crystal structure and molecular dynamics simulations

2021 ◽  
Author(s):  
Xiaodan Li ◽  
Karol Jan Nass ◽  
Ioana M Ilie ◽  
Manfred J Saller ◽  
Arnold J. M. Driessen ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Molecular Dynamics ◽  
Thermotoga Maritima ◽  
Membrane Surface ◽  
Transmembrane Helix ◽  
Specific Interaction ◽  
Md Simulations ◽  
Dual Function ◽  
Sec Translocon

The evolutionary conserved YidC is a unique dual-function protein that adopts insertase and chaperone conformations. The TM1 helix of Escherichia coli YidC mediates the interaction between the YidC chaperone and the Sec translocon. Here, we report the first crystal structure of Thermotoga maritima YidC (TmYidC) including the TM1 helix (PDB ID: 6Y86). The TM1 helix lies on the periplasmic side of the bilayer forming an angle of about 15 degrees with the membrane surface. Our functional studies suggest a role of TM1 for the species-specific interaction with the Sec translocon. The reconstitution data and the superimposition of TmYidC with known YidC structures suggest an active insertase conformation for YidC. Molecular dynamics (MD) simulations of TmYidC provide evidence that the TM1 helix acts as a membrane anchor for the YidC insertase and highlight the flexibility of the C1 region underlining its ability to switch between insertase and chaperone conformations. A structure-based model is proposed to rationalize how YidC performs the insertase and chaperone functions by re-positioning of the TM1 helix and the other structural elements.

scholarly journals Molecular Dynamics Simulation of Homo-DNA: The Role of Crystal Packing in Duplex Conformation

Crystals ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 532
Author(s):  
Jonathan H. Sheehan ◽  
Jarrod A. Smith ◽  
Pradeep S. Pallan ◽  
Terry P. Lybrand ◽  
Martin Egli
Keyword(s):  
Crystal Structure ◽  
Molecular Dynamics ◽  
Nucleic Acid ◽  
Base Pair ◽  
Crystal Packing ◽  
Md Simulations ◽  
Conformational Flexibility ◽  
Dynamics Simulation ◽  
Dna Duplex ◽  
Solution Studies

The (4′→6′)-linked DNA homolog 2′,3′-dideoxy-β-D-glucopyranosyl nucleic acid (dideoxy-glucose nucleic acid or homo-DNA) exhibits stable self-pairing of the Watson–Crick and reverse-Hoogsteen types, but does not cross-pair with DNA. Molecular modeling and NMR solution studies of homo-DNA duplexes pointed to a conformation that was nearly devoid of a twist and a stacking distance in excess of 4.5 Å. By contrast, the crystal structure of the homo-DNA octamer dd(CGAATTCG) revealed a right-handed duplex with average values for helical twist and rise of ca. 15° and 3.8 Å, respectively. Other key features of the structure were strongly inclined base-pair and backbone axes in the duplex with concomitant base-pair slide and cross-strand stacking, and the formation of a dimer across a crystallographic dyad with inter-duplex base swapping. To investigate the conformational flexibility of the homo-DNA duplex and a potential influence of lattice interactions on its geometry, we used molecular dynamics (MD) simulations of the crystallographically observed dimer of duplexes and an isolated duplex in the solution state. The dimer of duplexes showed limited conformational flexibility, and key parameters such as helical rise, twist, and base-pair slide exhibited only minor fluctuations. The single duplex was clearly more flexible by comparison and underwent partial unwinding, albeit without significant lengthening. Thus, base stacking was preserved in the isolated duplex and two adenosines extruded from the stack in the dimer of duplexes were reinserted into the duplex and pair with Ts in a Hoogsteen mode. Our results confirmed that efficient stacking in homo-DNA seen in the crystal structure of a dimer of duplexes was maintained in the separate duplex. Therefore, lattice interactions did not account for the different geometries of the homo-DNA duplex in the crystal and earlier models that resembled inclined ladders with large base-pair separations that precluded efficient stacking.

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.

scholarly journals Molecular dynamics simulations of the Cx26 hemichannel: Evaluation of structural models with Brownian dynamics

2011 ◽  
Vol 138 (5) ◽  
pp. 475-493 ◽  
Author(s):  
Taekyung Kwon ◽  
Andrew L. Harris ◽  
Angelo Rossi ◽  
Thaddeus A. Bargiello
Keyword(s):  
Crystal Structure ◽  
Molecular Dynamics ◽  
Posttranslational Modifications ◽  
Brownian Dynamics ◽  
Ion Selectivity ◽  
Physiological Role ◽  
Md Simulations ◽  
Cation Selectivity ◽  
Gap Junction Channel ◽  
Channel Properties

The recently published crystal structure of the Cx26 gap junction channel provides a unique opportunity for elucidation of the structure of the conductive connexin pore and the molecular determinants of its ion permeation properties (conductance, current–voltage [I-V] relations, and charge selectivity). However, the crystal structure was incomplete, most notably lacking the coordinates of the N-terminal methionine residue, which resides within the pore, and also lacking two cytosolic domains. To allow computational studies for comparison with the known channel properties, we completed the structure. Grand canonical Monte Carlo Brownian dynamics (GCMC/BD) simulations of the completed and the published Cx26 hemichannel crystal structure indicate that the pore is too narrow to permit significant ion flux. The GCMC/BD simulations predict marked inward current rectification and almost perfect anion selectivity, both inconsistent with known channel properties. The completed structure was refined by all-atom molecular dynamics (MD) simulations (220 ns total) in an explicit solvent and POPC membrane system. These MD simulations produced an equilibrated structure with a larger minimal pore diameter, which decreased the height of the permeation barrier formed by the N terminus. GCMC/BD simulations of the MD-equilibrated structure yielded more appropriate single-channel conductance and less anion/cation selectivity. However, the simulations much more closely matched experimentally determined I-V relations when the charge effects of specific co- and posttranslational modifications of Cx26 previously identified by mass spectrometry were incorporated. We conclude that the average equilibrated structure obtained after MD simulations more closely represents the open Cx26 hemichannel structure than does the crystal structure, and that co- and posttranslational modifications of Cx26 hemichannels are likely to play an important physiological role by defining the conductance and ion selectivity of Cx26 channels. Furthermore, the simulations and data suggest that experimentally observed heterogeneity in Cx26 I-V relations can be accounted for by variation in co- and posttranslational modifications.

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 Insights into the Polyhexamethylene Biguanide (PHMB) Mechanism of Action on Bacterial Membrane and DNA: A Molecular Dynamics Study

2020 ◽  
Author(s):  
Shahin Sowlati-Hashjin ◽  
Paola Carbone ◽  
Mikko Karttunen
Keyword(s):  
Molecular Dynamics ◽  
Electrostatic Interactions ◽  
Membrane Surface ◽  
Md Simulations ◽  
Phospholipid Bilayer ◽  
Phospholipid Membrane ◽  
Replication Process ◽  
Polyhexamethylene Biguanide ◽  
Phosphate Backbone ◽  
Pass Through

AbstractPolyhexamethylene biguanide (PHMB) is a cationic polymer with antimicrobial and antiviral properties. It has been commonly accepted that the antimicrobial activity is due the ability of PHMB to perforate the bacterial phospholipid membrane leading ultimately to its death. In this study we show by the means of atomistic molecular dynamics (MD) simulations that while the PHMB molecules attach to the surface of the phospholipid bilayer and partially penetrate it, they do not cause any pore formation at least within the microsecond simulation times. The polymers initially adsorb onto the membrane surface via the favourable electrostatic interactions between the phospholipid headgroups and the biguanide groups, and then partially penetrate the membrane slightly disrupting its structure. This, however, does not lead to the formation of any pores. The microsecond-scale simulations reveal that it is unlikely for PHMB to spontaneously pass through the phospholipid membrane. Our findings suggest that PHMB translocation across the bilayer may take place through binding to the phospholipids. Once inside the cell, the polymer can effectively ‘bind’ to DNA through extensive interactions with DNA phosphate backbone, which can potentially block the DNA replication process or activate DNA repair pathways.TOC Graphic

scholarly journals Biomolecular Solvation Structure Revealed by Molecular Dynamics Simulations

2018 ◽  
Author(s):  
Michael Wall ◽  
Gaetano Calabró ◽  
Christopher I. Bayly ◽  
David Mobley ◽  
Gregory Warren
Keyword(s):  
Crystal Structure ◽  
Molecular Dynamics ◽  
Neutron Diffraction ◽  
Water Structure ◽  
Md Simulations ◽  
Neutron Density ◽  
Macromolecular Crystallography ◽  
Field Development ◽  
Biomolecular Solvation ◽  
Dynamics Simulations

In order to compare ordered water positions from experiment with those from molecular dynamics (MD) simulations, a number of MD models of water structure in crystalline endoglucanase were calculated. The starting MD model was derived from a joint X-ray and neutron diffraction crystal structure, enabling the use of experimentally assigned protonation states. Simulations were performed in the crystalline state, using a periodic 2x2x2 supercell with explicit solvent. Water electron and neutron density maps were computed from MD trajectories using standard macromolecular crystallography methods. In one set of simulations, harmonic restraints were applied to bias the protein structure toward the crystal structure. For these simulations, the recall of crystallographic waters using strong peaks in the MD water electron density was excellent, and there also was substantial visual agreement between the boomerang-like wings of the neutron density and the crystalline water hydrogen positions. An unrestrained simulation also was performed. For this simulation, the recall of crystallographic waters was much lower. The results demonstrate that it is now possible to recover crystallographic water structure using restrained MD simulations, but that it is not yet reasonable to expect unrestrained MD simulations to do the same. Further development and generalization of MD water models for force field development, macromolecular crystallography, and medicinal chemistry applications is now warranted. In particular, the combination of room-temperature crystallography, neutron diffraction, and crystalline MD simulations promises to substantially advance modeling of biomolecular solvation.

scholarly journals The Role of ICL1 and H8 in Class B1 GPCRs; Implications for Receptor Activlation

2022 ◽  
Vol 12 ◽  
Author(s):  
Ian Winfield ◽  
Kerry Barkan ◽  
Sarah Routledge ◽  
Nathan J. Robertson ◽  
Matthew Harris ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
G Protein ◽  
Conformational Changes ◽  
Transmembrane Helix ◽  
Receptor Activation ◽  
Cgrp Receptor ◽  
Intracellular Loop ◽  
Glucagon Receptor ◽  
G Protein Coupled

The first intracellular loop (ICL1) of G protein-coupled receptors (GPCRs) has received little attention, although there is evidence that, with the 8th helix (H8), it is involved in early conformational changes following receptor activation as well as contacting the G protein β subunit. In class B1 GPCRs, the distal part of ICL1 contains a conserved R12.48KLRCxR2.46b motif that extends into the base of the second transmembrane helix; this is weakly conserved as a [R/H]12.48KL[R/H] motif in class A GPCRs. In the current study, the role of ICL1 and H8 in signaling through cAMP, iCa2+ and ERK1/2 has been examined in two class B1 GPCRs, using mutagenesis and molecular dynamics. Mutations throughout ICL1 can either enhance or disrupt cAMP production by CGRP at the CGRP receptor. Alanine mutagenesis identified subtle differences with regard elevation of iCa2+, with the distal end of the loop being particularly sensitive. ERK1/2 activation displayed little sensitivity to ICL1 mutation. A broadly similar pattern was observed with the glucagon receptor, although there were differences in significance of individual residues. Extending the study revealed that at the CRF1 receptor, an insertion in ICL1 switched signaling bias between iCa2+ and cAMP. Molecular dynamics suggested that changes in ICL1 altered the conformation of ICL2 and the H8/TM7 junction (ICL4). For H8, alanine mutagenesis showed the importance of E3908.49b for all three signal transduction pathways, for the CGRP receptor, but mutations of other residues largely just altered ERK1/2 activation. Thus, ICL1 may modulate GPCR bias via interactions with ICL2, ICL4 and the Gβ subunit.

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 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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