scholarly journals Patterns in Protein Flexibility: A Comparison of NMR “Ensembles”, MD Trajectories, and Crystallographic B-Factors

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1484
Author(s):  
Christopher Reinknecht ◽  
Anthony Riga ◽  
Jasmin Rivera ◽  
David A. Snyder
Keyword(s):  
Protein Flexibility ◽  
Molecular Machines ◽  
Md Simulations ◽  
Peptide Bond ◽  
Structure Calculation ◽  
Atomic Scale ◽  
Heavy Atoms ◽  
Structural Ensembles ◽  
Atomic Coordinates ◽  
Motional Behavior

Proteins are molecular machines requiring flexibility to function. Crystallographic B-factors and Molecular Dynamics (MD) simulations both provide insights into protein flexibility on an atomic scale. Nuclear Magnetic Resonance (NMR) lacks a universally accepted analog of the B-factor. However, a lack of convergence in atomic coordinates in an NMR-based structure calculation also suggests atomic mobility. This paper describes a pattern in the coordinate uncertainties of backbone heavy atoms in NMR-derived structural “ensembles” first noted in the development of FindCore2 (previously called Expanded FindCore: DA Snyder, J Grullon, YJ Huang, R Tejero, GT Montelione, Proteins: Structure, Function, and Bioinformatics 82 (S2), 219–230) and demonstrates that this pattern exists in coordinate variances across MD trajectories but not in crystallographic B-factors. This either suggests that MD trajectories and NMR “ensembles” capture motional behavior of peptide bond units not captured by B-factors or indicates a deficiency common to force fields used in both NMR and MD calculations.

scholarly journals Patterns in protein flexibility: a comparison of NMR “ensembles”, MD trajectories and crystallographic B-factors

2017 ◽  
Author(s):  
Anthony Riga ◽  
Jasmin Rivera ◽  
David A. Snyder
Keyword(s):  
Protein Flexibility ◽  
Molecular Machines ◽  
Md Simulations ◽  
Peptide Bond ◽  
Structure Calculation ◽  
Atomic Scale ◽  
Heavy Atoms ◽  
Structural Ensembles ◽  
Atomic Coordinates ◽  
Motional Behavior

AbstractProteins are molecular machines requiring flexibility to function. Crystallographic B-factors and Molecular Dynamics (MD) simulations both provide insights into protein flexibility on an atomic scale. Nuclear Magnetic Resonance (NMR) lacks a universally accepted analog of the B-factor, however, a lack of convergence in atomic coordinates in an NMR-based structure calculation also suggests atomic mobility. This paper describes a pattern in the coordinate uncertainties of backbone heavy atoms in NMR-derived structural “ensembles” first noted in the development of FindCore2 (previously called Expanded FindCore: DA Snyder, J Grullon, YJ Huang, R Tejero, GT Montelione,Proteins: Structure, Function, and Bioinformatics82 (S2), 219–230) and demonstrates that this pattern exists in coordinate variances across MD trajectories but not in crystallographic B-factors. This either suggests that MD trajectories and NMR “ensembles” capture motional behavior of peptide bond units not captured by B-factors or indicates a deficiency common to force fields used in both NMR and MD calculations. Additionally, a comparison of Cα B-factors with Cα coordinate variability in NMR “ensembles” and MD trajectories shows that NMR-derived coordinate uncertainties measure variability in atomic positions as well as crystallographic B-factors and superimpositions of MD trajectories do.

scholarly journals Porous Characteristics of Three-Dimensional Disordered Graphene Networks

Crystals ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 127
Author(s):  
YongChao Wang ◽  
YinBo Zhu ◽  
HengAn Wu
Keyword(s):  
Pore Size ◽  
Low Temperatures ◽  
Gas Adsorption ◽  
Three Dimensional ◽  
Md Simulations ◽  
Structural Features ◽  
Atomic Scale ◽  
Critical Factors ◽  
Chlorination Process ◽  
Porous Morphology

The porous characteristics of disordered carbons are critical factors to their performance on hydrogen storage and electrochemical capacitors. Even though the porous information can be estimated indirectly by gas adsorption experiments, it is still hard to directly characterize the porous morphology considering the complex 3D connectivity. To this end, we construct full-atom disordered graphene networks (DGNs) by mimicking the chlorination process of carbide-derived carbons using annealing-MD simulations, which could model the structure of disordered carbons at the atomic scale. The porous characteristics, including pore volume, pore size distribution (PSD), and specific surface area (SSA), were then computed from the coordinates of carbon atoms. From the evolution of structural features, pores grow dramatically during the formation of polyaromatic fragments and sequent disordered framework. Then structure is further graphitized while the PSD shows little change. For the obtained DGNs, the porosity, pore size, and SSA increase with decreasing density. Furthermore, SSA tends to saturate in the low-density range. The DGNs annealed at low temperatures exhibit larger SSA than high-temperature DGNs because of the abundant free edges.

scholarly journals Computational Insights into Substrate and Site Specificities, Catalytic Mechanism, and Protonation States of the Catalytic Asp Dyad ofβ-Secretase

Scientifica ◽  
2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Arghya Barman ◽  
Rajeev Prabhakar
Keyword(s):  
Catalytic Mechanism ◽  
Md Simulations ◽  
Peptide Bond ◽  
Docking Studies ◽  
In Silico Screening ◽  
Rate Determining Step ◽  
Rate Limiting Step ◽  
Beta Peptide ◽  
Structural Differences ◽  
Rate Limiting

In this review, information regarding substrate and site specificities, catalytic mechanism, and protonation states of the catalytic Asp dyad ofβ-secretase (BACE1) derived from computational studies has been discussed. BACE1 catalyzes the rate-limiting step in the generation of Alzheimer amyloid beta peptide through the proteolytic cleavage of the amyloid precursor protein. Due to its biological functioning, this enzyme has been considered as one of the most important targets for finding the cure for Alzheimer’s disease. Molecular dynamics (MD) simulations suggested that structural differences in the key regions (inserts A, D, and F and the 10s loop) of the enzyme are responsible for the observed difference in its activities towards the WT- and SW-substrates. The modifications in the flap, third strand, and insert F regions were found to be involved in the alteration in the site specificity of the glycosylphosphatidylinositol bound form of BACE1. Our QM and QM/MM calculations suggested that BACE1 hydrolyzed the SW-substrate more efficiently than the WT-substrate and that cleavage of the peptide bond occurred in the rate-determining step. The results from molecular docking studies showed that the information concerning a single protonation state of the Asp dyad is not enough to run an in silico screening campaign.

Atomically Informed Continuum Models for the Elastic Contact Properties of Hollow and Coated Rigid Cylinders at the Nanoscale

2017 ◽  
Vol 84 (3) ◽  
Author(s):  
Leon Gorelik ◽  
Dan Mordehai
Keyword(s):  
Contact Stiffness ◽  
Md Simulations ◽  
Atomic Scale ◽  
Continuum Models ◽  
Elastic Contact ◽  
Pressure Profiles ◽  
Hollow Cylinders ◽  
Coated Surfaces ◽  
The One ◽  
The Continuum

Understanding the mechanical properties of contacts at the nanoscale is key to controlling the strength of coated surfaces. In this work, we explore to which extent existing continuum models describing elastic contacts with coated surfaces can be extended to the nanoscale. Molecular dynamics (MD) simulations of hollow cylinders or coated rigid cylinders under compression are performed and compared with models at the continuum level, as two representative extreme cases of coating which is substantially harder or softer than the substrate, respectively. We show here that the geometry of the atomic-scale contact is essential to capture the contact stiffness, especially for hollow cylinders with high relative thicknesses and for coated rigid cylinders. The contact pressure profiles in atomic-scale contacts are substantially different than the one proposed in the continuum models for rounded contacts. On the basis of these results, we formulate models whose solution can be computed analytically for the contact stiffness in the two extreme cases, and show how to bridge between the atomic and continuum scales with atomically informed geometry of the contact.

Study on Nanoimprint Lithography of the Polymer Chains (CH2)n With Anti-Adhesion Layer on Stamp by Molecular Dynamics Method

2008 ◽  
Author(s):  
Quang-Cherng Hsu ◽  
Chien-Liang Lin ◽  
Te-Hua Fang
Keyword(s):  
Molecular Dynamics ◽  
Polymer Material ◽  
Nanoimprint Lithography ◽  
Minimum Energy ◽  
Md Simulations ◽  
Atomic Scale ◽  
Polymer Materials ◽  
Energy Status ◽  
Adhesion Layer ◽  
System Energy

This paper aims at the study on nanoimprint lithography (NIL) of the polymer material in (CH2)n Chains. The simulation codes were built based on molecular dynamics (MD) method for observing material deformation behaviors in atomic scale. The deformation mechanism of NIL of polymer material (CH2)n pressed by silicon stamp was first studied, by which the effects of critical punch tip width, imprint depth, temperature, and adhesion effect were studied. Next, the nanoimprint processes with stamp tips covered by anti-adhesion material, which is a self-assembled monolayer (SAM), were studied to compare to those processes without having anti-adhesion layer. When deforming polymer material at or above room temperature, adhesion problems occur between stamp and polymer. Polymer materials adhere to stamp more severe than they adhere to each others because potential energies between long chains of polymers are smaller than those between polymer and stamp. From the relation between system energy and stamp translation based on the MD simulations, the system energy increases when stamp moves gradually. When unloading, the system energy will return to its minimum energy status and remains stable. However, when punch leaves polymer materials, energy fluctuation occurs due to some polymer materials adhere to the stamp. Finally, the analysis of stamp with and without SAM based on the MD method was conducted and discussed.

scholarly journals Energy Penalties Enhance Flexible Receptor Docking in a Model Cavity

2021 ◽  
Author(s):  
Anna Sophia Kamenik ◽  
Isha Singh ◽  
Parnian Lak ◽  
Trent E Balius ◽  
Klaus R Liedl ◽  
...  
Keyword(s):  
Protein Flexibility ◽  
Md Simulations ◽  
High Energy ◽  
General Applicability ◽  
Penalty Term ◽  
Conformational Ensembles ◽  
X Ray Crystallography ◽  
Conformational Preferences ◽  
Energy Penalty ◽  
Cavity Opening

Protein flexibility remains a major challenge in library docking due to difficulties in sampling conformational ensembles with accurate probabilities. Here we use the model cavity site of T4 Lysozyme L99A to test flexible receptor docking with energy penalties from molecular dynamics (MD) simulations. Crystallography with larger and smaller ligands indicates that this cavity can adopt three major conformations, open, intermediate, and closed. Since smaller ligands typically bind better to the cavity site, we anticipate an energy penalty for cavity opening. To estimate its magnitude, we calculate conformational preferences from MD simulations. We find that including a penalty term is essential for retrospective ligand enrichment, otherwise high-energy states dominate the docking. We then prospectively docked a library of over 900,000 compounds for new molecules binding to each conformational state. Absent a penalty term, the open conformation dominated the docking results; inclusion of this term led to a balanced sampling of ligands against each state. High ranked molecules were experimentally tested by Tm-upshift and X-ray crystallography. From 33 selected molecules, we identified 18 new ligands and determined 13 crystal structures. Most interesting were those bound to the open cavity, where the buried site opens to bulk solvent. Here, highly unusual ligands for this cavity had been predicted, including large ligands with polar tails; these were confirmed both by binding and by crystallography. In docking, incorporating protein flexibility with thermodynamic weightings may thus access new ligand chemotypes. The MD approach to accessing and, crucially, weighting such alternative states may find general applicability.

scholarly journals 501Y.V2 Spike Protein Resists the Antibody in Atomistic Simulations

2021 ◽  
Author(s):  
Son Tung Ngo
Keyword(s):  
Structural Change ◽  
Antibody Fragment ◽  
Neutralizing Antibody ◽  
Md Simulations ◽  
Atomic Scale ◽  
Atomistic Simulations ◽  
S Protein ◽  
Mutation System ◽  
Biological Target ◽  
Antibody Resistance

<div> <p><a>SARS-CoV-2 Spike (S) protein is a major biological target for COVID-19 vaccine design. Unfortunately, recent reports indicated that Spike (S) protein mutations can lead to antibody resistance. </a>However, understanding the process is limited, especially at the atomic scale. The structural change of S protein and neutralizing antibody fragment (FAb) complexes was thus probed using molecular dynamics (MD) simulations. In particular, backbone RMSD of the 501Y.V2 complex was significantly larger than that of the WT implying a large structural change of the mutation system. Moreover, the mean of , CCS, and SASA are almost the same when compared two complexes, but the distribution of these values are absolutely different. Furthermore, the free energy landscape of the complexes was significantly changed when the 501Y.V2 variant was induced. The binding pose between S protein and FAb was thus altered. The FAb-binding affinity to S protein was thus reduced due to revealing over steered-MD (SMD) simulations. The observation is in good agreement with the respective experiment that the 501Y.V2 SARS-CoV-2 variant can escape from neutralizing antibody (NAb).</p> </div>

scholarly journals Maximizing resource usage in multifold molecular dynamics with rCUDA

2019 ◽  
Vol 34 (1) ◽  
pp. 5-19
Author(s):  
Javier Prades ◽  
Baldomero Imbernón ◽  
Carlos Reaño ◽  
Jorge Peña-García ◽  
Jose Pedro Cerón-Carrasco ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Drug Discovery ◽  
Graphics Processing Units ◽  
Materials Science ◽  
Dynamical Behavior ◽  
Md Simulations ◽  
Atomic Scale ◽  
Power Budget ◽  
Single Node ◽  
Time Required

The full-understanding of the dynamics of molecular systems at the atomic scale is of great relevance in the fields of chemistry, physics, materials science, and drug discovery just to name a few. Molecular dynamics (MD) is a widely used computer tool for simulating the dynamical behavior of molecules. However, the computational horsepower required by MD simulations is too high to obtain conclusive results in real-world scenarios. This is mainly motivated by two factors: (1) the long execution time required by each MD simulation (usually in the nanoseconds and microseconds scale, and beyond) and (2) the large number of simulations required in drug discovery to study the interactions between a large library of compounds and a given protein target. To deal with the former, graphics processing units (GPUs) have come up into the scene. The latter has been traditionally approached by launching large amounts of simulations in computing clusters that may contain several GPUs on each node. However, GPUs are targeted as a single node that only runs one MD instance at a time, which translates into low GPU occupancy ratios and therefore low throughput. In this work, we propose a strategy to increase the overall throughput of MD simulations by increasing the GPU occupancy through virtualized GPUs. We use the remote CUDA (rCUDA) middleware as a tool to decouple GPUs from CPUs, and thus enabling multi-tenancy of the virtual GPUs. As a working test in the drug discovery field, we studied the binding process of a novel flavonol to DNA with the GROningen MAchine for Chemical Simulations (GROMACS) MD package. Our results show that the use of rCUDA provides with a 1.21× speed-up factor compared to the CUDA counterpart version while requiring a similar power budget.

New View of Low-Temperature Sintering Phenomenon of Nanometer-Size Particles Based on Molecular Dynamics Study

MRS Advances ◽  
2016 ◽  
Vol 1 (30) ◽  
pp. 2167-2172
Author(s):  
Norie Matsubara ◽  
Shinji Munetoh ◽  
Osamu Furukimi
Keyword(s):  
Molecular Dynamics ◽  
Surface Layer ◽  
Diffusion Coefficient ◽  
Heating Temperature ◽  
Md Simulations ◽  
Atomic Scale ◽  
Self Diffusion ◽  
The Mean ◽  
The Relationship ◽  
Self Diffusion Coefficient

ABSTRACTIn this study, we have investigated a behavior of particle with diameter several ten nanometers size at the time of heating on an atomic scale by numerical analysis using the molecular dynamics (MD) simulation. On solving the equation of motion, the Langevin equation was adopted. The Finnis-Sinclair potential, which can well reproduce the mechanical properties of a BCC-metal, was used as the interatomic force. We determined the relationship between the melting point (Tm) of the nano-sized particles and its diameter by MD simulations. We have also investigated the self-diffusion coefficient of each atom-forming at a temperature larger or less than Tm of the submicron-size metal particles . As a result, even in case of heating at a temperature larger than Tm, the mean self-diffusion coefficient at the center of a particle was 10-7–10-6 cm2/sec. On the other hand, at the surface layer of the particle was two to three orders of magnitude larger than that at the center. Those particles were in a quasi-molten state. It is conceivable that the thickness of the surface layer can explain a phenomenon that sintering progresses as the heating temperature increases.

Annealing Kinetics of Single Displacement Cascades in Ni: An Atomic Scale Computer Simulation

1998 ◽  
Vol 540 ◽  
Author(s):  
A. Almazouzi ◽  
M. J. Caturla ◽  
T. Diaz de la Rubia ◽  
M. Victoria
Keyword(s):  
Interatomic Potential ◽  
Kinetic Monte Carlo ◽  
Scale Up ◽  
Md Simulations ◽  
Atomic Scale ◽  
Displacement Cascade ◽  
Atomistic Study ◽  
Kinetics Of

AbstractIn order to describe the long term evolution of the defects produced by a displacement cascade, Molecular dynamics (MD) and Kinetic Monte Carlo (KMC) methods are employed. Using an empirical Ni interatomic potential in MD, the damage resulting from primary knock-on atom (PKA) energies up to 30 keV has been simulated. The annealing kinetics and the fraction of freely migrating defects (FMD) are determined for each single displacement cascade, by a KMC code which is based on a set of parameters extracted mainly from MD simulations. It allows an atomistic study of the evolution of the initial damage over a time scale up to lOOs and the determination of the fraction of the defects that escape the KMC box, compared to those obtained by MD, as function of temperature and PKA energy. It has been found that this fraction depends strongly on the temperature but reaches a saturation value above stage V.

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