Search results for "molecular dynamics"

Experiments Meet Hydrophobic Mismatch: A Re-evaluation Of The Orientation Of Model Transmembrane Peptides From Solid-State NMR

2009

The basic physical rules underlying the organization of biological membranes can be gathered under the simple, but powerful, concept of hydrophobic mismatch. For example, the mutual adjustment of the lipid and protein hydrophobic lengths can be related with the existence of lipid rafts and explain discrete secretory pathways in the Golgi apparatus. The orientation of membrane protein fragments is predicted to follow the same hydrophobic mismatch principles, as illustrated by some experiments and molecular dynamics simulations. However, this appears to be challenged by results of solid-state 2H NMR experiments on model transmembrane peptides, displaying tilt angle values unexpectedly small a…

Construction and characterization of models of hypercrosslinked polystyrene

2012

A simple algorithm involving classical molecular dynamics (MD) simulations is here suggested to build up models of hypercrosslinked polystyrene showing macroporous structure. The algorithm is composed by three consecutive stages: MD simulation of a single polystyrene coil, crosslink formation, and finally relaxation of the structure. The models, which are differentiated by the crosslinker concentration in the initial polystyrene chain, can be characterized by employing tools of the small angle neutron scattering analysis and procedures associated to the crosslinking algorithm, which allows one to discriminate among the different kinds of crosslinks between phenyl rings and to calculate the …

Liquid structure and dynamics in the choline acetate:urea 1:2 deep eutectic solvent

2021

We report on the thermodynamic, structural, and dynamic properties of a recently proposed deep eutectic solvent, formed by choline acetate (ChAc) and urea (U) at the stoichiometric ratio 1:2, hereinafter indicated as ChAc:U. Although the crystalline phase melts at 36-38 degrees C depending on the heating rate, ChAc:U can be easily supercooled at sub-ambient conditions, thus maintaining at the liquid state, with a glass-liquid transition at about -50 degrees C. Synchrotron high energy x-ray scattering experiments provide the experimental data for supporting a reverse Monte Carlo analysis to extract structural information at the atomistic level. This exploration of the liquid structure of ChA…

Molecular Modeling and Dynamics of the transcriptionfactor NF-kB complexed with IkB

2009

Scalable Constant pH Molecular Dynamics in GROMACS

2022

Molecular dynamics (MD) computer simulations are used routinely to compute atomistic trajectories of complex systems. Systems are simulated in various ensembles, depending on the experimental conditions one aims to mimic. While constant energy, temperature, volume, and pressure are rather straightforward to model, pH, which is an equally important parameter in experiments, is more difficult to account for in simulations. Although a constant pH algorithm based on the λ-dynamics approach by Brooks and co-workers [Kong, X.; Brooks III, C. L. J. Chem. Phys.1996, 105, 2414–2423] was implemented in a fork of the GROMACS molecular dynamics program, uptake has been rather limited, presumably due to…

Inhibition of the Cysteine Protease Human Cathepsin L by Triazine Nitriles: Amide⋅⋅⋅Heteroarene π-Stacking Interactions and Chalcogen Bonding in the …

2016

We report an extensive "heteroarene scan" of triazine nitrile ligands of the cysteine protease human cathepsin L (hCatL) to investigate π-stacking on the peptide amide bond Gly67-Gly68 at the entrance of the S3 pocket. This heteroarene⋅⋅⋅peptide bond stacking was supported by a co-crystal structure of an imidazopyridine ligand with hCatL. Inhibitory constants (Ki ) are strongly influenced by the diverse nature of the heterocycles and specific interactions with the local environment of the S3 pocket. Binding affinities vary by three orders of magnitude. All heteroaromatic ligands feature enhanced binding by comparison with hydrocarbon analogues. Predicted energetic contributions from the ori…

Exploring the non-covalent ligand-binding mechanism on immunoproteasome by enhanced Molecular Dynamics

2021

Selective inhibition of immunoproteasome is a valuable strategy to treat autoimmune and inflammatory diseases, and hematologic malignancies. In particular, non-covalent inhibition is strongly desirable because it is free of the drawbacks and side effects associated with covalent inhibition. Recently, a new series of amide derivatives with Ki values in the low/submicromolar ranges toward the β1i subunit have been identified as non-covalent inhibitors 1 . We investigated the binding mechanism of the most potent and selective inhibitor (1) to elucidate the steps from the ligand entrance into the binding pocket to the ligand-induced conformational changes. We carried out a total of 400ns of MD-…

In situ structural analysis of SARS-CoV-2 spike reveals flexibility mediated by three hinges

2020

Flexible spikes The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein enables viral entry into host cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor and is a major target for neutralizing antibodies. About 20 to 40 spikes decorate the surface of virions. Turoňová et al. now show that the spike is flexibly connected to the viral surface by three hinges that are well protected by glycosylation sites. The flexibility imparted by these hinges may explain how multiple spikes act in concert to engage onto the flat surface of a host cell. Science, this issue p. 203

Nanomechanical cleavage of molybdenum disulphide atomic layers.

2014

The discovery of two-dimensional materials became possible due to the mechanical cleavage technique. Despite its simplicity, the as-cleaved materials demonstrated surprising macrocontinuity, high crystalline quality and extraordinary mechanical and electrical properties that triggered global research interest. Here such cleavage processes and associated mechanical behaviours are investigated by a direct in situ transmission electron microscopy probing technique, using atomically thin molybdenum disulphide layers as a model material. Our technique demonstrates layer number selective cleavage, from a monolayer to double layer and up to 23 atomic layers. In situ observations combined with mole…

Molecular modeling approaches in the discovery of new drugs for anti-cancer therapy: the investigation of p53-MDM2 interaction and its inhibition by …

2010

The mdm2 oncogene product, MDM2, is an ubiquitin protein ligase that inhibits the transcriptional activity of the tumor suppressor p53 and promotes its degradation. About 50% of all human cancers present mutations or deletions in the TP53 gene. In the remaining half of all human neoplasias that express the wild-type protein, aberrations of p53 regula- tors, such as MDM2, account for p53 inhibition. For this reason, designing small-molecule inhibitors of the p53-MDM2 protein-protein interaction is a promising strategy for the treatment of cancers retaining wild-type p53. The development of inhibitors has been challenging. Although many small-molecule MDM2 inhibitors have shown potent in vitr…