Ball-and-Stick Local Elevation Umbrella Sampling: Molecular Simulations Involving Enhanced Sampling within Conformational or Alchemical Subspaces of Low Internal Dimensionalities, Minimal Irrelevant Volumes, and Problem-Adapted Geometries

2010 ◽  
Vol 6 (9) ◽  
pp. 2622-2646 ◽  
Author(s):  
Halvor S. Hansen ◽  
Philippe H. Hünenberger
Keyword(s):  
Molecular Simulations ◽  
Umbrella Sampling ◽  
Enhanced Sampling

scholarly journals An Efficient GaMD Multi-Level Enhanced Sampling Strategy: Application to Polarizable Force Fields Simulations of Large Biological Systems

2021 ◽  
Author(s):  
Fréderic Célerse ◽  
Theo Jaffrelot-Inizan ◽  
Louis Lagardère ◽  
Olivier Adjoua ◽  
Pierre Monmarché ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Adaptive Sampling ◽  
Sampling Strategy ◽  
Umbrella Sampling ◽  
Potential Of Mean Force ◽  
Enhanced Sampling ◽  
Polarizable Force Field ◽  
Accelerated Molecular Dynamics ◽  
Polarizable Force Fields ◽  
Multi Level

We detail a novel multi-level enhanced sampling strategy grounded on Gaussian accelerated Molecular Dynamics (GaMD). First, we propose a GaMD multi-GPUs-accelerated implementation within the Tinker-HP molecular dynamics package. We then introduce the new "dual-water" mode and its use with the flexible AMOEBA polarizable force field. By adding harmonic boosts to the water stretching and bonding terms, it accelerates the solvent-solute interactions while enabling speedups thanks to the use of fast multiple--timestep integrators. To further reduce time-to-solution, we couple GaMD to Umbrella Sampling (US). The GaMD—US/dual-water approach is tested on the 1D Potential of Mean Force (PMF) of the CD2-CD58 system (168000 atoms) allowing the AMOEBA PMF to converge within 1 kcal/mol of the experimental value. Finally, Adaptive Sampling (AS) is added enabling AS-GaMD capabilities but also the introduction of the new Adaptive Sampling--US--GaMD (ASUS--GaMD) scheme. The highly parallel ASUS--GaMD setup decreases time to convergence by respectively 10 and 20 compared to GaMD--US and US.

scholarly journals An Efficient GaMD Multi-Level Enhanced Sampling Strategy for Polarizable Force Fields Simulations of Large Biological Systems

2021 ◽  
Author(s):  
Fréderic Célerse ◽  
Theo Jaffrelot-Inizan ◽  
Louis Lagardère ◽  
Olivier Adjoua ◽  
Pierre Monmarché ◽  
...  
Keyword(s):  
Adaptive Sampling ◽  
Sampling Strategy ◽  
Umbrella Sampling ◽  
Potential Of Mean Force ◽  
Enhanced Sampling ◽  
Polarizable Force Field ◽  
Accelerated Molecular Dynamics ◽  
Polarizable Force Fields ◽  
Solute Interactions ◽  
Multi Level

We introduce a novel multi-level enhanced sampling strategy grounded on Gaussian accelerated Molecular Dynamics (GaMD). First, we propose a GaMD multi-GPUs -accelerated implementation within Tinker-HP. For the specific use with the flexible AMOEBA polarizable force field (PFF), we introduce the new "dual–water" GaMD mode. By adding harmonic boosts to the water stretching and bonding terms, it accelerates the solvent-solute interactions while enabling speedups with fast multiple–timestep integrators. To further reduce time-to-solution, we couple GaMD to Umbrella Sampling (US). The GaMD—US/dual–water approach is tested on the 1D Potential of Mean Force (PMF) of the CD2–CD58 system (168000 atoms) allowing the AMOEBA PMF to converge within 1 kcal/mol of the experimental value. Finally, Adaptive Sampling (AS) is added enabling AS–GaMD capabilities but also the introduction of the new Adaptive Sampling–US–GaMD (ASUS–GaMD) scheme. The highly parallel ASUS–GaMD setup decreases time to convergence by respectively 10 and 20 compared to GaMD–US and US.

scholarly journals Identification of rare Lewis oligosaccharide conformers in aqueous solution using enhanced sampling molecular dynamics

2017 ◽  
Author(s):  
Irfan Alibay ◽  
Kepa K. Burusco ◽  
Neil J. Bruce ◽  
Richard A. Bryce
Keyword(s):  
Molecular Dynamics ◽  
Aqueous Solution ◽  
Md Simulations ◽  
Umbrella Sampling ◽  
Biological Action ◽  
Sialyl Lewis X ◽  
Enhanced Sampling ◽  
Sialyl Lewis ◽  
Aqueous Solvent ◽  
A Minor

<p>Determining the conformations accessible to carbohydrate ligands in aqueous solution is important for understanding their biological action. In this work, we evaluate the conformational free energy surfaces of Lewis oligosaccharides in explicit aqueous solvent using a multidimensional variant of the swarm-enhanced sampling molecular dynamics (msesMD) method; we compare with multi-microsecond unbiased MD simulations, umbrella sampling and accelerated MD approaches. For the sialyl Lewis A tetrasaccharide, msesMD simulations in aqueous solution predict conformer landscapes in general agreement with the other biased methods and with triplicate unbiased 10 ms trajectories; these simulations find a predominance of closed conformer and a range of low occupancy open forms. The msesMD simulations also suggest closed-to-open transitions in the tetrasaccharide are facilitated by changes in ring puckering of its GlcNAc residue away from the <sup>4</sup>C<sub>1</sub> form, in line with previous work. For sialyl Lewis X tetrasaccharide, msesMD simulations predict a minor population of an open form in solution, corresponding to a rare lectin-bound pose observed crystallographically. Overall, from comparison with biased MD calculations, we find that triplicate 10 ms unbiased MD simulations may not be enough to fully sample glycan conformations in aqueous solution. However, the computational efficiency and intuitive approach of the msesMD method suggest potential for its application in glycomics as a tool for analysis of oligosaccharide conformation.</p>

scholarly journals Extended Phase-Space Methods for Enhanced Sampling in Molecular Simulations: A Review

2015 ◽  
Vol 3 ◽  
Author(s):  
Hiroshi Fujisaki ◽  
Kei Moritsugu ◽  
Yasuhiro Matsunaga ◽  
Tetsuya Morishita ◽  
Luca Maragliano
Keyword(s):  
Phase Space ◽  
Molecular Simulations ◽  
Extended Phase Space ◽  
Enhanced Sampling ◽  
Extended Phase ◽  
Phase Space Methods

scholarly journals Conformational ensemble of human α-synuclein physiological form predicted by molecular simulations

2016 ◽  
Vol 18 (8) ◽  
pp. 5702-5706 ◽  
Author(s):  
G. Rossetti ◽  
F. Musiani ◽  
E. Abad ◽  
D. Dibenedetto ◽  
H. Mouhib ◽  
...  
Keyword(s):  
Protein Dynamics ◽  
Molecular Simulations ◽  
Intramolecular Interactions ◽  
Conformational Ensemble ◽  
Enhanced Sampling ◽  
Post Translational Modification ◽  
Α Helix

Enhanced sampling simulations of N-terminally acetylated human α-synuclein suggest that the post-translational modification leads to the formation of a transient amphipathic α-helix altering protein dynamics at the N-terminal and intramolecular interactions.

scholarly journals Chemically Accurate Relative Folding Stability of RNA Hairpins from Molecular Simulations

2018 ◽  
Author(s):  
Louis G. Smith ◽  
Zhen Tan ◽  
Aleksandar Spasic ◽  
Debapratim Dutta ◽  
Leslie A. Salas-Estrada ◽  
...  
Keyword(s):  
Free Energy ◽  
Molecular Simulations ◽  
Umbrella Sampling ◽  
Reaction Coordinate ◽  
Free Energy Change ◽  
Energy Change ◽  
Random Coil ◽  
Free Energies ◽  
Rna Hairpins ◽  
Rna Hairpin

AbstractThis study describes a comparison between melts and simulated stabilities of the same RNAs that could be used to benchmark RNA force fields, and potentially to determine future melt-ing experiments. Using umbrella sampling molecular simulations of three 12-nucleotide RNA hairpin stem loops, for which there are experimentally determined free energies of unfold-ing, we projected unfolding onto the reaction coordinate of end to end (5′ to 3′ hydroxyl oxygen) distance. We estimate the free energy change of the transition from the native con-formation to a fully extended conformation—the stretched state—with no hydrogen bonds between non-neighboring bases. Each simulation was performed four times using the AM-BER FF99+bsc0+χOL3 force field and each window, spaced at 1 Å intervals, was sampled for 1 μs, for a total of 552 μs of simulation. We compared differences in the simulated free energy changes to analogous differences in free energies from optical melting experiments using ther-modynamic cycles where the free energy change between stretched and random coil sequences is assumed to be sequence independent. The differences between experimental and simulated ΔΔG° are on average 1.00 ± 0.66 kcal/mol, which is chemically accurate and suggests analo-gous simulations could be used predictively. We also report a novel method to identify where replica free energies diverge along the reaction coordinate, thus indicating where additional sampling would most improve convergence. We conclude by discussing methods to more economically perform such simulations.

scholarly journals Biomolecular conformational changes and ligand binding: from kinetics to thermodynamics

2017 ◽  
Vol 8 (9) ◽  
pp. 6466-6473 ◽  
Author(s):  
Yong Wang ◽  
João Miguel Martins ◽  
Kresten Lindorff-Larsen
Keyword(s):  
Ligand Binding ◽  
Conformational Changes ◽  
Molecular Simulations ◽  
Kinetic Properties ◽  
Enhanced Sampling ◽  
Biomolecular Systems

Biomolecular systems such as protein–ligand complexes are governed by thermodynamic and kinetic properties that may be estimated at the same time through enhanced-sampling molecular simulations.

scholarly journals Assignment of the resting state of the secondary active transporter BetP by integrating spectroscopic measurements and molecular simulations

2018 ◽  
Author(s):  
Vanessa Leone ◽  
Izabela Waclawska ◽  
Caroline Koshy ◽  
Katharina Kossman ◽  
Monika Sharma ◽  
...  
Keyword(s):  
Double Resonance ◽  
Molecular Simulations ◽  
Enhanced Sampling ◽  
Experimental Conditions ◽  
Physiological Conditions ◽  
Data Comparison ◽  
Osmotic Stress Response ◽  
Biochemical Studies ◽  
Transport Cycle ◽  
Crystallographic Structures

The glycine betaine symporter BetP regulates the osmotic stress response of Corynebacterium glutamicum, a soil bacterium used extensively in biotechnology. Although BetP is a homotrimer, biochemical studies have shown that each protomer is able to transport its substrate independently. Crystallographic structures of BetP have been determined in several conformations, seemingly capturing outward-open, inward-open and occluded states, both loaded with the substrate and in the apo form. However, it has been challenging to establish a correspondence between each of these structures and specific states in the mechanism of the transporter under more physiological conditions. To this end, we examined the dynamics of spin-labelled BetP using pulsed electron-electron double resonance (PELDOR) under different stimuli. We then carried out molecular simulations of structures of the BetP monomer to interpret the PELDOR data, using the enhanced-sampling methodology EBMetaD [Marinelli & Faraldo-Gomez, 2015, Biophys J 108(12):2779-2782], whereby the dynamics of the protein are minimally biased so as to reproduce the experimental data. Comparison of the magnitude of the biasing work required for different input structures permitted us to assign them to specific states of the transport cycle under each of the experimental conditions. In particular, this analysis showed that BetP adopts inward-facing conformations in the presence of excess sodium, and a mixture of states when betaine is added. These studies better delineate the major conformations adopted by BetP in its transport cycle, and therefore provide important insights into its mechanism. More broadly, we illustrate how integrative simulations can aid interpretation of ambiguous structural and spectroscopic data on membrane proteins.

scholarly journals An Efficient GaMD Multi-Level Enhanced Sampling Strategy: Application to Polarizable Force Fields Simulations of Large Biological Systems

2021 ◽  
Author(s):  
Fréderic Célerse ◽  
Theo Jaffrelot-Inizan ◽  
Louis Lagardère ◽  
Olivier Adjoua ◽  
Pierre Monmarché ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Adaptive Sampling ◽  
Force Fields ◽  
Biological Systems ◽  
Sampling Strategy ◽  
Umbrella Sampling ◽  
Potential Of Mean Force ◽  
Enhanced Sampling ◽  
Polarizable Force Fields ◽  
Multi Level

We introduce a novel multi-level enhanced sampling strategy grounded on Gaussian accelerated Molecular Dynamics (GaMD). First, we propose a GaMD multi-GPUs-accelerated implementation within the Tinker-HP molecular dynamics package. We introduce the new "dual-water" mode and its use with the flexible AMOEBA polarizable force field.By adding harmonic boosts to the water stretching and bonding terms, it accelerates the solvent-solute interactions while enabling speedups thanks to the use of fast multiple--timestep integrators. To further reduce time-to-solution, we couple GaMD to Umbrella Sampling (US). The GaMD—US/dual--water approach is tested on the 1D Potential of Mean Force (PMF) of the solvated CD2--CD58 system (168000 atoms) allowing the AMOEBA PMF to converge within 1 kcal/mol of the experimental value. Finally, Adaptive Sampling (AS) is added enabling AS-GaMD capabilities but also the introduction of the new Adaptive Sampling--US--GaMD (ASUS-GaMD) scheme. The highly parallel ASUS--GaMD setup decreases time to convergence by respectively 10 and 20 times compared to GaMD-US and US. Overall, beside the acceleration of PMF computations, Tinker-HP now allows for the simultaneous use of Adaptive Sampling and GaMD-"dual water" enhanced sampling approaches increasing the applicability of polarizable force fields to large scale simulations of biological systems.

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