scholarly journals KEAP1 Cancer Mutants: A Large-Scale Molecular Dynamics Study of Protein Stability

2021 ◽  
Vol 22 (10) ◽  
pp. 5408
Author(s):  
Carter Wilson ◽  
Megan Chang ◽  
Mikko Karttunen ◽  
Wing-Yiu Choy
Keyword(s):  
Molecular Dynamics ◽  
Large Scale ◽  
Md Simulations ◽  
Covalent Modification ◽  
Additional Insight ◽  
New Class ◽  
Kelch Domain ◽  
Cancer Mutations ◽  
Mutagenic Effects ◽  
Insight Into

We have performed 280 μs of unbiased molecular dynamics (MD) simulations to investigate the effects of 12 different cancer mutations on Kelch-like ECH-associated protein 1 (KEAP1) (G333C, G350S, G364C, G379D, R413L, R415G, A427V, G430C, R470C, R470H, R470S and G476R), one of the frequently mutated proteins in lung cancer. The aim was to provide structural insight into the effects of these mutants, including a new class of ANCHOR (additionally NRF2-complexed hypomorph) mutant variants. Our work provides additional insight into the structural dynamics of mutants that could not be analyzed experimentally, painting a more complete picture of their mutagenic effects. Notably, blade-wise analysis of the Kelch domain points to stability as a possible target of cancer in KEAP1. Interestingly, structural analysis of the R470C ANCHOR mutant, the most prevalent missense mutation in KEAP1, revealed no significant change in structural stability or NRF2 binding site dynamics, possibly indicating an covalent modification as this mutant’s mode of action.

scholarly journals Large-Scale Molecular Dynamics Simulations of Homogeneous Nucleation of Pure Aluminium

Metals ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 1217 ◽  
Author(s):  
Papanikolaou ◽  
Salonitis ◽  
Jolly ◽  
Frank
Keyword(s):  
Molecular Dynamics ◽  
Large Scale ◽  
Solidification Process ◽  
Md Simulations ◽  
Pure Aluminium ◽  
3 Dimensional ◽  
Hexagonal Close Packed ◽  
Simulation Domain ◽  
Dynamics Simulations ◽  
Insight Into

Despite the continuous and remarkable development of experimental techniques for the investigation of microstructures and the growth of nuclei during the solidification of metals, there are still unknown territories around this topic. The solidification in nanoscale can be effectively investigated by means of molecular dynamics (MD) simulations which can provide a deep insight into the mechanisms of the formation of nuclei and the induced crystal structures. In this study, MD simulations were performed to investigate the solidification of pure Aluminium and the effects of the cooling rate on the final properties of the solidified material. A large number of Aluminium atoms were used in order to investigate the grain growth over time and the formation of stacking faults during solidification. The number of face-centred cubic (FCC), hexagonal close-packed (HCP) and body-centred cubic (BCC) was recorded during the evolution of the process to illustrate the nanoscale mechanisms initiating solidification. The current investigation also focuses on the exothermic nature of the solidification process which has been effectively captured by means of MD simulations using 3 dimensional representations of the kinetic energy across the simulation domain.

Topological connectivity analysis of accumulated radiation damage from multiple molecular dynamics recoil cascades

2012 ◽  
Vol 1475 ◽  
Author(s):  
Henry R. Foxhall ◽  
John H. Harding ◽  
Karl P. Travis
Keyword(s):  
Molecular Dynamics ◽  
Kinetic Energy ◽  
Radiation Damage ◽  
Large Scale ◽  
Structural Evolution ◽  
Md Simulations ◽  
Recoil Atom ◽  
Connectivity Analysis ◽  
Topological Connectivity ◽  
Insight Into

ABSTRACTThe results of sequential large-scale molecular dynamics (MD) simulations of radiation damage cascades in Gd2Ti2O7 and Gd2Zr2O7 are presented. Twelve alpha recoil cascades, each due to a recoil atom with 40 keV of kinetic energy, are performed in both materials and a stark contrast in behaviour observed. Topological connectivity analysis is used to analyse the structural evolution of the two systems. Our results provide important insight into accumulation of disorder in pyrochlore-structured ceramics.

scholarly journals Investigation of Molecular Details of Keap1-Nrf2 Inhibitors Using Molecular Dynamics and Umbrella Sampling Techniques

Molecules ◽  
2019 ◽  
Vol 24 (22) ◽  
pp. 4085 ◽  
Author(s):  
Ashwini Machhindra Londhe ◽  
Changdev Gorakshnath Gadhe ◽  
Sang Min Lim ◽  
Ae Nim Pae
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Binding Pocket ◽  
Umbrella Sampling ◽  
Valuable Insight ◽  
Protein Protein Interaction ◽  
Kelch Domain ◽  
Insight Into

In this study, we investigate the atomistic details of Keap1-Nrf2 inhibitors by in-depth modeling techniques, including molecular dynamics (MD) simulations, and the path-based free energy method of umbrella sampling (US). The protein–protein interaction (PPI) of Keap1-Nrf2 is implicated in several neurodegenerative diseases like cancer, diabetes, and cardiomyopathy. A better understanding of the five sub-pocket binding sites for Nrf2 (ETGE and DLG motifs) inside the Kelch domain would expedite the inhibitor design process. We selected four protein–ligand complexes with distinct co-crystal ligands and binding occupancies inside the Nrf2 binding site. We performed 100 ns of MD simulation for each complex and analyzed the trajectories. From the results, it is evident that one ligand (1VV) has flipped inside the binding pocket, whereas the remaining three were stable. We found that Coulombic (Arg483, Arg415, Ser363, Ser508, and Ser602) and Lennard–Jones (Tyr525, Tyr334, and Tyr572) interactions played a significant role in complex stability. The obtained binding free energy values from US simulations were consistent with the potencies of simulated ligands. US simulation highlight the importance of basic and aromatic residues in the binding pocket. A detailed description of the dissociation process brings valuable insight into the interaction of the four selected protein–ligand complexes, which could help in the future to design more potent PPI inhibitors.

Molecular Dynamics Simulation of a Pullout Test on a Carbon Nanotube in a Polymer Matrix

2014 ◽  
Vol 1700 ◽  
pp. 61-66
Author(s):  
Guttormur Arnar Ingvason ◽  
Virginie Rollin
Keyword(s):  
Molecular Dynamics ◽  
Polymer Matrix ◽  
Large Scale ◽  
Md Simulations ◽  
Dynamics Simulation ◽  
Atomistic Simulations ◽  
Polymer Molecules ◽  
Molecular Potential ◽  
Pull Out ◽  
Walled Carbon Nanotubes

ABSTRACTAdding single walled carbon nanotubes (SWCNT) to a polymer matrix can improve the delamination properties of the composite. Due to the complexity of polymer molecules and the curing process, few 3-D Molecular Dynamics (MD) simulations of a polymer-SWCNT composite have been run. Our model runs on the Large-scale Atomic/Molecular Massively Parallel Simulator (LAMMPS), with a COMPASS (Condensed phase Optimized Molecular Potential for Atomistic Simulations Studies) potential. This potential includes non-bonded interactions, as well as bonds, angles and dihedrals to create a MD model for a SWCNT and EPON 862/DETDA (Diethyltoluenediamine) polymer matrix. Two simulations were performed in order to test the implementation of the COMPASS parameters. The first one was a tensile test on a SWCNT, leading to a Young’s modulus of 1.4 TPa at 300K. The second one was a pull-out test of a SWCNT from an originally uncured EPON 862/DETDA matrix.

On the use of jerk and snap in condition monitoring of machinery – review and case studies

2021 ◽  
Vol 63 (8) ◽  
pp. 457-464
Author(s):  
S Lahdelma
Keyword(s):  
Condition Monitoring ◽  
Large Scale ◽  
Early Stage ◽  
Time Derivative ◽  
Additional Insight ◽  
Rolling Bearings ◽  
Monitoring Applications ◽  
Derivatives Of ◽  
Insight Into ◽  
Peak Value

The time derivatives of acceleration offer a great advantage in detecting impact-causing faults at an early stage in condition monitoring applications. Defective rolling bearings and gears are common faults that cause impacts. This article is based on extensive real-world measurements, through which large-scale machines have been studied. Numerous laboratory experiments provide additional insight into the matter. A practical solution for detecting faults with as few features as possible is to measure the root mean square (RMS) velocity according to the standards in the frequency range from 10 Hz to 1000 Hz and the peak value of the second time derivative of acceleration, ie snap. Measuring snap produces good results even when the upper cut-off frequency is as low as 2 kHz or slightly higher. This is valuable information when planning the mounting of accelerometers.

scholarly journals Antimicrobial action of the cationic peptide, chrysophsin-3: a coarse-grained molecular dynamics study

Soft Matter ◽  
2018 ◽  
Vol 14 (15) ◽  
pp. 2796-2807 ◽  
Author(s):  
Andrea Catte ◽  
Mark R. Wilson ◽  
Martin Walker ◽  
Vasily S. Oganesyan
Keyword(s):  
Molecular Dynamics ◽  
Large Scale ◽  
Md Simulations ◽  
Antimicrobial Action ◽  
Coarse Grained ◽  
Cationic Peptide ◽  
Coarse Grained Molecular Dynamics

Antimicrobial action of a cationic peptide is modelled by large scale MD simulations.

scholarly journals Molecular dynamics simulations for genetic interpretation in protein coding regions: where we are, where to go and when

2019 ◽  
Author(s):  
Juan J Galano-Frutos ◽  
Helena García-Cebollada ◽  
Javier Sancho
Keyword(s):  
Molecular Dynamics ◽  
Amino Acid ◽  
Large Scale ◽  
Binary Classification ◽  
Chemical Properties ◽  
Md Simulations ◽  
Single Amino Acid ◽  
Medical Decision ◽  
Evolutionary Information ◽  
Protein Variants

Abstract The increasing ease with which massive genetic information can be obtained from patients or healthy individuals has stimulated the development of interpretive bioinformatics tools as aids in clinical practice. Most such tools analyze evolutionary information and simple physical–chemical properties to predict whether replacement of one amino acid residue with another will be tolerated or cause disease. Those approaches achieve up to 80–85% accuracy as binary classifiers (neutral/pathogenic). As such accuracy is insufficient for medical decision to be based on, and it does not appear to be increasing, more precise methods, such as full-atom molecular dynamics (MD) simulations in explicit solvent, are also discussed. Then, to describe the goal of interpreting human genetic variations at large scale through MD simulations, we restrictively refer to all possible protein variants carrying single-amino-acid substitutions arising from single-nucleotide variations as the human variome. We calculate its size and develop a simple model that allows calculating the simulation time needed to have a 0.99 probability of observing unfolding events of any unstable variant. The knowledge of that time enables performing a binary classification of the variants (stable-potentially neutral/unstable-pathogenic). Our model indicates that the human variome cannot be simulated with present computing capabilities. However, if they continue to increase as per Moore’s law, it could be simulated (at 65°C) spending only 3 years in the task if we started in 2031. The simulation of individual protein variomes is achievable in short times starting at present. International coordination seems appropriate to embark upon massive MD simulations of protein variants.

scholarly journals 1,2-Αnnulated Adamantane Heterocyclic Derivatives as Anti-Influenza Α Virus Agents

2019 ◽  
Vol 92 (2) ◽  
pp. 211-228 ◽  
Author(s):  
Vasiliki Pardali ◽  
Erofili Giannakopoulou ◽  
Athina Konstantinidi ◽  
Antonios Kolocouris ◽  
Grigoris Zoidis
Keyword(s):  
Molecular Dynamics ◽  
Influenza A ◽  
Md Simulations ◽  
Biological Evaluation ◽  
Propanoic Acid ◽  
M2 Protein ◽  
Additional Insight ◽  
Structure Activity ◽  
Heterocyclic Derivatives ◽  
Pharmacological Potential

In this report we review our results on the development of 1,2-annulated adamantane heterocyclic derivatives and we discuss the structure-activity relationships obtained from their biological evaluation against influenza A virus. We have designed and synthesized numerous potent 1,2-annulated adamantane analogues of amantadine and rimantadine against influenza A targeting M2 protein the last 20 years. For their synthesis we utilized the key intermediates 2-(2-oxoadamantan-1-yl)acetic acid and 3-(2-oxoadamantan-1-yl)propanoic acid, which were obtained by a simple, fast and efficient synthetic protocol. The latter involved the treatment of protoadamantanone with different electrophiles and a carbon-skeleton rearrangement. These ketoesters offered a new pathway to the synthesis of 1,2-disubstituted adamantanes, which constitute starting materials for many molecules with pharmacological potential, such as the 1,2-annulated adamantane heterocyclic derivatives. To obtain additional insight for their binding to M2 protein three structurally similar 1,2-annulated adamantane piperidines, differing in nitrogen position, were studied using molecular dynamics (MD) simulations in palmitoyl-oleoyl-phosphatidyl-choline (POPC) hydrated bilayers.

scholarly journals Hydrogenation Dynamics of Biphenylene Carbon (Graphenylene) Membranes

MRS Advances ◽  
2017 ◽  
Vol 2 (29) ◽  
pp. 1571-1576
Author(s):  
Vinicius Splugues ◽  
Pedro Alves da Silva Autreto ◽  
Douglas S. Galvao
Keyword(s):  
Molecular Dynamics ◽  
Large Scale ◽  
Materials Science ◽  
Md Simulations ◽  
Structural Transformations ◽  
Extensive Study ◽  
Massively Parallel ◽  
Porous Membranes ◽  
Two Dimensional ◽  
Reactive Force

ABSTRACTThe advent of graphene created a revolution in materials science. Because of this there is a renewed interest in other carbon-based structures. Graphene is the ultimate (just one atom thick) membrane. It has been proposed that graphene can work as impermeable membrane to standard gases, such argon and helium. Graphene-like porous membranes, but presenting larger porosity and potential selectivity would have many technological applications. Biphenylene carbon (BPC), sometimes called graphenylene, is one of these structures. BPC is a porous two-dimensional (planar) allotrope carbon, with its pores resembling typical sieve cavities and/or some kind of zeolites. In this work, we have investigated the hydrogenation dynamics of BPC membranes under different conditions (hydrogenation plasma density, temperature, etc.). We have carried out an extensive study through fully atomistic molecular dynamics (MD) simulations using the reactive force field ReaxFF, as implemented in the well-known Large-scale Atomic/Molecular Massively Parallel Simulator (LAMMPS) code. Our results show that the BPC hydrogenation processes exhibit very complex patterns and the formation of correlated domains (hydrogenated islands) observed in the case of graphene hydrogenation was also observed here. MD results also show that under hydrogenation BPC structure undergoes a change in its topology, the pores undergoing structural transformations and extensive hydrogenation can produce significant structural damages, with the formation of large defective areas and large structural holes, leading to structural collapse.

scholarly journals Indentation-induced plastic behaviour of nanotwinned Cu/high entropy alloy FeCoCrNi nanolaminate: an atomic simulation

RSC Advances ◽  
2020 ◽  
Vol 10 (16) ◽  
pp. 9187-9192 ◽  
Author(s):  
Hui Feng ◽  
Jingwen Tang ◽  
Haotian Chen ◽  
Yuanyuan Tian ◽  
Qihong Fang ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Large Scale ◽  
Md Simulations ◽  
High Entropy Alloy ◽  
High Entropy ◽  
Atomic Simulation ◽  
Layer Number ◽  
Plastic Behaviour

Using large-scale molecular dynamics (MD) simulations, the effects of interface and layer number in the nanoindentation response of experimentally observed nanotwinned Cu/high entropy alloy (HEA) FeCoCrNi nanolaminate are studied.

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