Mechanism of Helix Nucleation and Propagation:  Microscopic View from Microsecond Time Scale MD Simulations

2005 ◽  
Vol 109 (43) ◽  
pp. 20064-20067 ◽  
Author(s):  
Luca Monticelli ◽  
D. Peter Tieleman ◽  
Giorgio Colombo
Keyword(s):  
Time Scale ◽  
Md Simulations ◽  
Helix Nucleation

What Is the Time Scale for α-Helix Nucleation?

2011 ◽  
Vol 133 (17) ◽  
pp. 6809-6816 ◽  
Author(s):  
David De Sancho ◽  
Robert B. Best
Keyword(s):  
Time Scale ◽  
Helix Nucleation ◽  
Α Helix

UNDERSTANDING THE MOLECULAR MECHANISM OF BINDING MODES OF AURORA A INHIBITORS BY LONG TIME SCALE GPU DYNAMICS

2013 ◽  
Vol 12 (08) ◽  
pp. 1341003 ◽  
Author(s):  
TING FU ◽  
XUE WU ◽  
ZHILONG XIU ◽  
JINGUANG WANG ◽  
LIU YIN ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Time Scale ◽  
Binding Free Energy ◽  
Cancer Therapeutics ◽  
Md Simulations ◽  
Aurora A Kinase ◽  
Binding Modes ◽  
Aurora A ◽  
Long Time ◽  
The Individual

Inhibition of Aurora A kinase interaction is considered to be a promising approach for the discovery of new molecularly targeted cancer therapeutics. In this study, the binding mechanisms of two different inhibitors with a contrasting binding affinity to Aurora A were investigated by long time scale GPU molecular dynamics (MD) simulations coupled with molecular mechanics-Poisson–Boltzmann/generalized Born surface area (MM-PB/GBSA) method. The results showed that the predicted binding free energies of these two complexes were consistent with the experimental data. Through analyzing the individual energy components of binding free energy, we found that the van der Waals contribution was the main force to drive the inhibitor–protein binding and the electrostatic contribution was also a crucial factor for the inhibitor–Aurora A binding. The structural analysis demonstrated that the inhibitor HPM could produce more hydrophobic interaction contacts with Aurora A than that of 2JZ, and the loss of key hydrogen bonds between the inhibitor and residue Arg137 in the hinge region of Aurora A was another important reason for the weaker binding affinity of 2JZ to Aurora A. This study sheds more light on the development of the efficient inhibitors targeting the Aurora A.

Finding Transition Pathways

2006 ◽  
Author(s):  
Vasily Bulatov ◽  
Wei Cai
Keyword(s):  
Time Scales ◽  
Time Scale ◽  
Md Simulations ◽  
Small Time ◽  
Metastable States ◽  
Integration Step ◽  
Acceptance Ratio ◽  
Atomic Displacements ◽  
Simulation Efficiency ◽  
The Many

As was discussed in Chapter 2, stable and accurate numerical integration of the MD equations of motion demands a small time step. In MD simulations of solids, the integration step is usually of the order of one femtosecond (10−15 s). For this reason, the time horizon ofMDsimulations of solids rarely exceeds one nanosecond (10−9 s). On the other hand, dislocation behaviors of interest typically occur on time scales of milliseconds (10−3 s) or longer. Such behaviors remain out of reach for direct MD simulations. Time-scale limits of a similar nature also exist in MC simulations. For instance, the magnitude of the atomic displacements in the Metropolis algorithm has to be sufficiently small to ensure a reasonable acceptance ratio, which results in a slow exploration of the configurational space. This disparity of time scales can be traced to certain topographical features of the potential-energy function of the many-body system, typically consisting of deep energy basins separated by high energy barriers. The system spends most of its time wandering around within the energy basins (metastable states) only rarely interrupted by transitions from one basin to another. Whereas the long-term evolution of a solid results from transitions between the metastable states, direct MDand MC simulations spend most of the time faithfully tracing the unimportant fluctuations within the energy basins. In this sense, most of the computing cycles are wasted, leading to very low simulation efficiency. Because the transition rates decrease exponentially with the increasing barrier heights and decreasing temperature, this problem of time-scale disparity can be severe.

A Study of Local and Extended Migration of H and Defects in a-Si by Molecular Dynamics Simulations

1996 ◽  
Vol 420 ◽  
Author(s):  
Peter A. Fedders
Keyword(s):  
Molecular Dynamics ◽  
Ab Initio ◽  
Molecular Dynamics Simulations ◽  
Time Scale ◽  
Md Simulations ◽  
Fast Time ◽  
Fast Time Scale ◽  
Defect Interaction ◽  
Free Sample ◽  
Dynamics Simulations

AbstractWe report on extensive molecular dynamics (MD) simulations on a-Si:H for up to 5 Ps using the ab initio code of Sankey and Drabold. The supercells contain about 70 atoms and only one defect in order to minimize defect-defect interaction. Simulations on supercell samples that originally contain one bond centered (BC) H in an otherwise defect free sample exhibit BC to BC diffusion as in c-Si. However, we also observe localized motion of defects and H atoms on a very fast time scale that probably has been observed in several experiments.

scholarly journals Passive Internalization of Bioactive β-Casein Peptides into Phospholipid (POPC) Bilayers. Free Energy Landscapes from Unbiased Equilibrium MD Simulations at μs-Time Scale

2020 ◽  
Author(s):  
Eduardo Jardón-Valadez ◽  
Charles H. Chen ◽  
Mariano García-Garibay ◽  
Judith Jiménez-Guzmán ◽  
Martin B. Ulmschneider
Keyword(s):  
Free Energy ◽  
Time Scale ◽  
Md Simulations ◽  
Energy Landscapes ◽  
Free Energy Landscapes

High-resolution MD simulation studies to get mechanistic insights into the urea-induced denaturation of human Sphingosine kinase 1

2021 ◽  
Vol 21 ◽  
Author(s):  
Faez Iqbal Khan ◽  
Shahid Ali ◽  
Wenjing Chen ◽  
Farah Anjum ◽  
Alaa Shafie ◽  
...  
Keyword(s):  
Time Scale ◽  
Md Simulation ◽  
Structural Changes ◽  
Sphingosine Kinase ◽  
Md Simulations ◽  
Sphingosine Kinase 1 ◽  
Cellular Survival ◽  
Constant Form ◽  
The Impact ◽  
Unfolding Kinetics

Background: Sphingosine kinase 1 (SPhK1) is a crucial signaling enzyme involved in cell proliferation, cellular survival, stimulation of angiogenesis, and apoptosis prevention. Recently, we have reported the unfolding kinetics of SPhK1 using molecular dynamics (MD) simulation, circular dichroism and fluorescence spectroscopy. We found that SPhK1 showed a biphasic unfolding with an intermediate state (~ 4.0 M urea). Objective: We aim to understand the impact of MD simulation duration on the structure, function and dynamics of proteins. In order to get deeper insights into the folding mechanism an extended MD simulation is required. Method: Here, we extended the MD simulations time scale from 100 to 300 ns on SPhK1 at increasing urea concentration to explore structural changes in the SPhK1. Results: The results suggested a constant form of the unfolding of SPhK1 upon extending the simulation time scale at different urea concentrations. Furthermore, we showed step by step unfolding and percentage of secondary structure contents in SPhK1 under the influence of urea at each concentration. Conclusion: The results from the current work revealed a uniform pattern of the SPhK1 unfolding at different urea concentrations. This study provides deeper mechanistic insights into the urea-induced denaturation of SPhK1.

Long-Time Scale Fluctuations of Human Prion Protein Determined by Restrained MD Simulations

Biochemistry ◽  
2011 ◽  
Vol 50 (47) ◽  
pp. 10192-10194 ◽  
Author(s):  
Massih Khorvash ◽  
Guillaume Lamour ◽  
Jörg Gsponer
Keyword(s):  
Prion Protein ◽  
Time Scale ◽  
Md Simulations ◽  
Long Time ◽  
Human Prion Protein ◽  
Restrained Md

scholarly journals Towards Convergence in Folding Simulations of RNA Tetraloops: Comparison of Enhanced Sampling Techniques and Effects of Force Field Corrections

2021 ◽  
Author(s):  
Vojtech Mlynsky ◽  
Michal Janecek ◽  
Petra Kuhrova ◽  
Thorben Frohlking ◽  
Michal Otyepka ◽  
...  
Keyword(s):  
Time Scale ◽  
Md Simulations ◽  
Sampling Techniques ◽  
Enhanced Sampling ◽  
Free Energies ◽  
Native State ◽  
Good Convergence ◽  
Empirical Potentials ◽  
Folding Simulations ◽  
Established Technique

Atomistic molecular dynamics (MD) simulations represent established technique for investigation of RNA structural dynamics. Despite continuous development, contemporary RNA simulations still suffer from suboptimal accuracy of empirical potentials (force fields, ffs) and sampling limitations. Development of efficient enhanced sampling techniques is important for two reasons. First, they allow to overcome the sampling limitations and, second, they can be used to quantify ff imbalances provided they reach a sufficient convergence. Here, we study two RNA tetraloops (TLs), namely the GAGA and UUCG motifs. We perform extensive folding simulations and calculate folding free energies (ΔGfold) with the aim to compare different enhanced sampling techniques and to test several modifications of the nonbonded terms extending the AMBER OL3 RNA ff. We demonstrate that replica exchange solute tempering (REST2) simulations with 12-16 replicas do not show any sign of convergence even when extended to time scale of 120 μs per replica. However, combination of REST2 with well-tempered metadynamics (ST-MetaD) achieves good convergence on a time-scale of 5-10 μs per replica, improving the sampling efficiency by at least two orders of magnitude. Effects of ff modifications on ΔGfold energies were initially explored by the reweighting approach and then validated by new simulations. We tested several manually-prepared variants of gHBfix potential which improve stability of the native state of both TLs by up to ~2 kcal/mol. This is sufficient to conveniently stabilize the folded GAGA TL while the UUCG TL still remains under-stabilized. Appropriate adjustment of van der Waals parameters for C-H...O5' base-phosphate interaction are also shown to be capable of further stabilizing the native states of both TLs by ~0.6 kcal/mol.

scholarly journals Structural Dynamics of Monomeric α-Synuclein on the PS-µS Time Scale Derived from MD Simulations

2018 ◽  
Vol 114 (3) ◽  
pp. 77a
Author(s):  
Reinhard Klement ◽  
Timo Graen ◽  
Asaf Grupi ◽  
Elisha Haas ◽  
Helmut Grubmueller
Keyword(s):  
Structural Dynamics ◽  
Time Scale ◽  
Md Simulations
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