Large scale molecular dynamics simulation of native and mutant dihydropteroate synthase–sulphanilamide complexes suggests the molecular basis for dihydropteroate synthase drug resistance

2005 ◽  
Vol 363 (1833) ◽  
pp. 2055-2073 ◽  
Author(s):  
Fabrizio Giordanetto ◽  
Philip W Fowler ◽  
Mansoor Saqi ◽  
Peter V Coveney
Keyword(s):  
Molecular Dynamics ◽  
Drug Resistance ◽  
Molecular Basis ◽  
Large Scale ◽  
Homology Modelling ◽  
Dynamics Simulation ◽  
Dihydropteroate Synthase ◽  
Enzymatic Transformation ◽  
Sulpha Drug ◽  
Dynamics Simulations

Antibiotic resistance is hampering the efficacy of drugs in the treatment of several pathological infections. Dihydropteroate synthase (DHPS) has been targeted by sulphonamide inhibitors for the past 60 years and has developed different amino acid mutations to survive sulpha drug action. We couple homology modelling techniques and massively parallel molecular dynamics simulations to study both the drug-bound and apo forms of native and mutant DHPS. Simulations of the complex between sulphanilamide and Streptomyces pneumoniae , DHPS shows how sulphanilamide is able to position itself close to 6-hydroxymethyl-7, 8-dihydropteridine-phosphate in a suitable position for the enzymatic transformation whereas in the mutant complex the sulpha drug is expelled from the catalytic site. Our simulations, therefore, provide insight into the molecular basis for drug resistance with S. pneumoniae DHPS.

LARGE-SCALE MOLECULAR-DYNAMICS SIMULATION OF 19 BILLION PARTICLES

2004 ◽  
Vol 15 (01) ◽  
pp. 193-201 ◽  
Author(s):  
KAI KADAU ◽  
TIMOTHY C. GERMANN ◽  
PETER S. LOMDAHL
Keyword(s):  
Molecular Dynamics ◽  
Large Scale ◽  
Dynamics Simulation ◽  
Atomistic Simulations ◽  
Huge Number ◽  
Physical Problems ◽  
Efficient Data ◽  
Dynamics Simulations ◽  
Large Scale Simulations ◽  
Efficient Data Analysis

We have performed parallel large-scale molecular-dynamics simulations on the QSC-machine at Los Alamos. The good scalability of the SPaSM code is demonstrated together with its capability of efficient data analysis for enormous system sizes up to 19 000 416 964 particles. Furthermore, we introduce a newly-developed graphics package that renders in a very efficient parallel way a huge number of spheres necessary for the visualization of atomistic simulations. These abilities pave the way for future atomistic large-scale simulations of physical problems with system sizes on the μ-scale.

scholarly journals Influence of laser nanostructured diamond tools on the cutting behavior of silicon by molecular dynamics simulation

RSC Advances ◽  
2017 ◽  
Vol 7 (25) ◽  
pp. 15596-15612 ◽  
Author(s):  
Houfu Dai ◽  
Genyu Chen ◽  
Shaobo Li ◽  
Qihong Fang ◽  
Bang Hu
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Large Scale ◽  
Diamond Tool ◽  
Single Crystal Silicon ◽  
Dynamics Simulation ◽  
Crystal Silicon ◽  
Nanometric Cutting ◽  
Dynamics Simulations ◽  
Cutting Behavior

In this study, a series of large-scale molecular dynamics simulations have been performed to study the nanometric cutting of single crystal silicon with a laser-fabricated nanostructured diamond tool.

Molecular Dynamics Simulation of the Thermal Conductivity of Silicon-Germanene Nanoribbon (SiGeNR): A Comparison with Silicene Nanoribbon (SiNR) and Germanene Nanoribbon (GeNR)

2015 ◽  
Vol 1105 ◽  
pp. 285-289 ◽  
Author(s):  
Jessa Mae P. Tagalog ◽  
Cachey Girly Alipala ◽  
Giovanni J. Paylaga ◽  
Naomi T. Paylaga ◽  
Rolando V. Bantaculo
Keyword(s):  
Thermal Conductivity ◽  
Molecular Dynamics ◽  
Silicon Germanium ◽  
Large Scale ◽  
Room Temperature ◽  
Single Layer ◽  
Dynamics Simulation ◽  
Two Dimensional ◽  
Silicon And Germanium ◽  
Dynamics Simulations

This study examines the nature of thermal transport properties of single layer two-dimensional honeycomb structures of silicon-germanene nanoribbon (SiGeNR), silicene nanoribbon (SiNR) and germanene nanoribbon (GeNR) which have not yet been characterized experimentally. SiGeNR, SiNR and GeNR are the allotropes of silicon-germanium, silicon and germanium, respectively, withsp2hybridization. The thermal conductivity of the materials has been investigated using Tersoff potential through LAMMPS (Large-scale Atomic/Molecular Massively Parallel Simulator) by performing the molecular-dynamics simulations. The temperature is varied (50 K, 77 K, 150 K, 300 K, 500 K, 700 K, 1000 K, and 1200 K) with fixed nanoribbon dimension of 50 nm × 10 nm. The length is also varied (10 nm, 20 nm, 30 nm, 40 nm, and 50 nm) while the temperature is fixed at room temperature and the width is also fixed at 10 nm. The obtained results showed that the thermal conductivity of SiGeNR at room temperature is approximately 10 times higher than GeNR and approximately 6 times higher compared to SiNR. The thermal conductivity increases as the temperature is increased from 50 K – 300 K, and as the temperature is further increased, the thermal conductivity decreases with temperature. Moreover, the thermal conductivity in SiGeNR, SiNR, and GeNR increases as the length is being increased. Predicting new features of SiGeNR, SiNR and GeNR open new possibilities for nanoelectronic device applications of group IV two-dimensional materials.

Drug resistance mechanisms of three mutations V32I, I47V and V82I in HIV-1 protease toward inhibitors probed by molecular dynamics simulations and binding free energy predictions

RSC Advances ◽  
2016 ◽  
Vol 6 (63) ◽  
pp. 58573-58585 ◽  
Author(s):  
Jianzhong Chen
Keyword(s):  
Molecular Dynamics ◽  
Drug Resistance ◽  
Free Energy ◽  
Binding Free Energy ◽  
Resistance Mechanisms ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Probe Drug ◽  
Dynamics Simulations ◽  
Hiv 1

Molecular dynamics simulation and binding free energy calculations were used to probe drug resistance of HIV-1 protease mutations toward inhibitors.

scholarly journals The crystal structure of the tetrameric human vasohibin-1–SVBP complex reveals a variable arm region within the structural core

2020 ◽  
Vol 76 (10) ◽  
pp. 993-1000
Author(s):  
Akihito Ikeda ◽  
Seia Urata ◽  
Tadashi Ando ◽  
Yasuhiro Suzuki ◽  
Yasufumi Sato ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Molecular Dynamics ◽  
Molecular Basis ◽  
Regulatory Mechanism ◽  
Hydrophobic Interactions ◽  
Terminal Region ◽  
Dynamics Simulation ◽  
Mutual Exchange ◽  
Structure Determinations ◽  
Dynamics Simulations

Vasohibins regulate angiogenesis, tumor growth, metastasis and neuronal differentiation. They form a complex with small vasohibin-binding protein (SVBP) and show tubulin tyrosine carboxypeptidase activity. Recent crystal structure determinations of vasohibin–SVBP complexes have provided a molecular basis for complex formation, substrate binding and catalytic activity. However, the regulatory mechanism and dynamics of the complex remain elusive. Here, the crystal structure of the VASH1–SVBP complex and a molecular-dynamics simulation study are reported. The overall structure of the complex was similar to previously reported structures. Importantly, however, the structure revealed a domain-swapped heterotetramer that was formed between twofold symmetry-related molecules. This heterotetramerization was stabilized by the mutual exchange of ten conserved N-terminal residues from the VASH1 structural core, which was intramolecular in other structures. Interestingly, a comparison of this region with previously reported structures revealed that the patterns of hydrogen bonding and hydrophobic interactions vary. In the molecular-dynamics simulations, differences were found between the heterotetramer and heterodimer, where the fluctuation of the N-terminal region in the heterotetramer was suppressed. Thus, heterotetramer formation and flexibility of the N-terminal region may be important for enzyme activity and regulation.

Variation in aspects of cysteine proteinase catalytic mechanism deduced by spectroscopic observation of dithioester intermediates, kinetic analysis and molecular dynamics simulations

2001 ◽  
Vol 357 (2) ◽  
pp. 343-352 ◽  
Author(s):  
James D. REID ◽  
Syeed HUSSAIN ◽  
Suneal K. SREEDHARAN ◽  
Tamara S. F. BAILEY ◽  
Surapong PINITGLANG ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Steady State ◽  
Molecular Dynamics Simulations ◽  
Large Scale ◽  
Catalytic Mechanism ◽  
Cysteine Proteinase ◽  
Salt Bridge ◽  
Dynamics Simulation ◽  
Active Centre ◽  
Dynamics Simulations

The possibility of a slow post-acylation conformational change during catalysis by cysteine proteinases was investigated by using a new chromogenic substrate, N-acetyl-Phe-Gly methyl thionoester, four natural variants (papain, caricain, actinidin and ficin), and stopped-flow spectral analysis to monitor the pre-steady state formation of the dithioacylenzyme intermediates and their steady state hydrolysis. The predicted reversibility of acylation was demonstrated kinetically for actinidin and ficin, but not for papain or caricain. This difference between actinidin and papain was investigated by modelling using QUANTA and CHARMM. The weaker binding of hydrophobic substrates, including the new thionoester, by actinidin than by papain may not be due to the well-known difference in their S2-subsites, whereby that of actinidin in the free enzyme is shorter due to the presence of Met211. Molecular dynamics simulation suggests that during substrate binding the sidechain of Met211 moves to allow full access of a Phe sidechain to the S2-subsite. The highly anionic surface of actinidin may contribute to the specificity difference between papain and actinidin. During subsequent molecular dynamics simulations the P1 product, methanol, diffuses rapidly (over < 8ps) out of papain and caricain but ‘lingers’ around the active centre of actinidin. Uniquely in actinidin, an Asp142–Lys145 salt bridge allows formation of a cavity which appears to constrain diffusion of the methanol away from the catalytic site. The cavity then undergoes large scale movements (over 4.8 Å) in a highly correlated manner, thus controlling the motions of the methanol molecule. The changes in this cavity that release the methanol might be those deduced kinetically.

Parallel Computation of Large-Scale Molecular Dynamics Simulations

2006 ◽  
Vol 326-328 ◽  
pp. 341-344 ◽  
Author(s):  
Sung Jin Kwon ◽  
Young Min Lee ◽  
Se Young Im
Keyword(s):  
Molecular Dynamics ◽  
Parallel Computation ◽  
Large Scale ◽  
Dynamics Simulation ◽  
New Approach ◽  
Atomistic Systems ◽  
Computation Scheme ◽  
Continuum Scale ◽  
Dynamics Simulations ◽  
Macroscopic Continuum

A large-scale parallel computation is extremely important for MD (molecular dynamics) simulation, particularly in dealing with atomistic systems with realistic size comparable to macroscopic continuum scale. We present a new approach for parallel computation of MD simulation. The entire system domain under consideration is divided into many Eulerian subdomains, each of which is surrounded with its own buffer layer and to which its own processor is assigned. This leads to an efficient tracking of each molecule, even when the molecules move out of its subdomain. Several numerical examples are provided to demonstrate the effectiveness of this computation scheme.

Deducing density and strength of nanocrystalline Ta and diamond under extreme conditions from X-ray diffraction

2019 ◽  
Vol 26 (2) ◽  
pp. 413-421 ◽  
Author(s):  
Y. Y. Zhang ◽  
M. X. Tang ◽  
Y. Cai ◽  
J. C. E ◽  
S. N. Luo
Keyword(s):  
Shock Wave ◽  
Molecular Dynamics ◽  
Large Scale ◽  
Density Measurement ◽  
Dynamics Simulation ◽  
Extreme Conditions ◽  
X Ray Diffraction ◽  
X Ray ◽  
Diffraction Patterns ◽  
Dynamics Simulations

In situ X-ray diffraction with advanced X-ray sources offers unique opportunities for investigating materials properties under extreme conditions such as shock-wave loading. Here, Singh's theory for deducing high-pressure density and strength from two-dimensional (2D) diffraction patterns is rigorously examined with large-scale molecular dynamics simulations of isothermal compression and shock-wave compression. Two representative solids are explored: nanocrystalline Ta and diamond. Analysis of simulated 2D X-ray diffraction patterns is compared against direct molecular dynamics simulation results. Singh's method is highly accurate for density measurement (within 1%) and reasonable for strength measurement (within 10%), and can be used for such measurements on nanocrystalline and polycrystalline solids under extreme conditions (e.g. in the megabar regime).

Combustion Driven by Fragment-based Ab Initio Molecular Dynamics Simulation

2019 ◽  
Author(s):  
Liqun Cao ◽  
Jinzhe Zeng ◽  
Mingyuan Xu ◽  
Chih-Hao Chin ◽  
Tong Zhu ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Ab Initio ◽  
Large Scale ◽  
Methane Combustion ◽  
Combustion Method ◽  
Dynamics Simulation ◽  
Ab Initio Molecular Dynamics ◽  
Computational Time ◽  
Combustion Mechanism ◽  
Daily Lives

Combustion is a kind of important reaction that affects people's daily lives and the development of aerospace. Exploring the reaction mechanism contributes to the understanding of combustion and the more efficient use of fuels. Ab initio quantum mechanical (QM) calculation is precise but limited by its computational time for large-scale systems. In order to carry out reactive molecular dynamics (MD) simulation for combustion accurately and quickly, we develop the MFCC-combustion method in this study, which calculates the interaction between atoms using QM method at the level of MN15/6-31G(d). Each molecule in systems is treated as a fragment, and when the distance between any two atoms in different molecules is greater than 3.5 Å, a new fragment involved two molecules is produced in order to consider the two-body interaction. The deviations of MFCC-combustion from full system calculations are within a few kcal/mol, and the result clearly shows that the calculated energies of the different systems using MFCC-combustion are close to converging after the distance thresholds are larger than 3.5 Å for the two-body QM interactions. The methane combustion was studied with the MFCC-combustion method to explore the combustion mechanism of the methane-oxygen system.

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