Folding Thermodynamics and Mechanism of Five Trp-Cage Variants from Replica-Exchange MD Simulations with RSFF2 Force Field

AbstractAlzheimer’s disease is histologically marked by fibrils of Amyloid beta (Aβ) peptide within the extracellular matrix. Fibrils themselves are benign compared to the cytotoxicity of the oligomers and pre-fibrillary aggregates. The conformational space and structural ensembles of Aβ peptides and their oligomers in solution are inherently disordered and proven to be challenging to study. Optimum force field selection for molecular dynamics (MD) simulations and the biophysical relevance of results are still unknown. We compared the conformational space of the Aβ(1–40) dimers by 300 ns replica exchange MD simulations at physiological temperature (310 K) using: the AMBER-ff99sb-ILDN, AMBER-ff99sb*-ILDN, AMBER-ff99sb-NMR, and CHARMM22* force fields. Statistical comparisons of simulation results to experimental data and previously published simulations utilizing the CHARMM22* and CHARMM36 force fields were performed. All force fields yield sampled ensembles of conformations with collision cross sectional areas for the dimer that are statistically significantly larger than experimental results. All force fields, with the exception of AMBER-ff99sb-ILDN (8.8±6.4%) and CHARMM36 (2.7±4.2%), tend to overestimate the α-helical content compared to experimental CD (5.3±5.2%). Using the AMBER-ff99sb-NMR force field resulted in the greatest degree of variance (41.3±12.9%). Except for the AMBER-ff99sb-NMR force field, the others tended to under estimate the expected amount of β-sheet and over estimate the amount of turn/bend/random coil conformations. All force fields, with the exception AMBER-ff99sb-NMR, reproduce a theoretically expected β-sheet-turn-β-sheet conformational motif, however, only the CHARMM22* and CHARMM36 force fields yield results compatible with collapse of the central and C-terminal hydrophobic cores from residues 17-21 and 30-36. Although analyses of essential subspace sampling showed only minor variations between force fields, secondary structures of lowest energy conformers are different.

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Folding simulation of Trp-cage utilizing a new AMBER compatible force field with coupled main chain torsions

Journal of Theoretical and Computational Chemistry ◽

10.1142/s0219633614500266 ◽

2014 ◽

Vol 13 (04) ◽

pp. 1450026 ◽

Cited By ~ 4

Author(s):

Lirong Mou ◽

Xiangyu Jia ◽

Ya Gao ◽

Yongxiu Li ◽

John Z. H. Zhang ◽

...

Keyword(s):

Force Field ◽

Main Chain ◽

Md Simulations ◽

Replica Exchange ◽

Hydrophobic Core ◽

Native Structure ◽

Folding Simulation ◽

Torsion Potential ◽

Folding Simulations ◽

Α Helix

A newly developed AMBER compatible force field with coupled backbone torsion potential terms (AMBER032D) is utilized in a folding simulation of a mini-protein Trp-cage. Through replica exchange and direct molecular dynamics (MD) simulations, a multi-step folding mechanism with a synergetic folding of the hydrophobic core (HPC) and the α-helix in the final stage is suggested. The native structure has the lowest free energy and the melting temperature predicted from the specific heat capacity Cvis only 12 K higher than the experimental measurement. This study, together with our previous study, shows that AMBER032Dis an accurate force field that can be used for protein folding simulations.

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Starting Structure Dependence of NMR Order Parameters Derived from MD Simulations: Implications for Judging Force-Field Quality

Biophysical Journal ◽

10.1529/biophysj.108.132811 ◽

2008 ◽

Vol 95 (1) ◽

pp. L04-L06 ◽

Cited By ~ 29

Author(s):

Alrun N. Koller ◽

Harald Schwalbe ◽

Holger Gohlke

Keyword(s):

Force Field ◽

Md Simulations ◽

Order Parameters ◽

Structure Dependence ◽

Field Quality

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A hierarchical Bayesian framework for force field selection in molecular dynamics simulations

Philosophical Transactions of The Royal Society A Mathematical Physical and Engineering Sciences ◽

10.1098/rsta.2015.0032 ◽

2016 ◽

Vol 374 (2060) ◽

pp. 20150032 ◽

Cited By ~ 20

Author(s):

S. Wu ◽

P. Angelikopoulos ◽

C. Papadimitriou ◽

R. Moser ◽

P. Koumoutsakos

Keyword(s):

Experimental Data ◽

Molecular Dynamics ◽

Force Field ◽

Computational Cost ◽

Md Simulations ◽

Bayesian Framework ◽

Underlying Structure ◽

Hierarchical Bayesian ◽

Wide Range ◽

Selection Of

We present a hierarchical Bayesian framework for the selection of force fields in molecular dynamics (MD) simulations. The framework associates the variability of the optimal parameters of the MD potentials under different environmental conditions with the corresponding variability in experimental data. The high computational cost associated with the hierarchical Bayesian framework is reduced by orders of magnitude through a parallelized Transitional Markov Chain Monte Carlo method combined with the Laplace Asymptotic Approximation. The suitability of the hierarchical approach is demonstrated by performing MD simulations with prescribed parameters to obtain data for transport coefficients under different conditions, which are then used to infer and evaluate the parameters of the MD model. We demonstrate the selection of MD models based on experimental data and verify that the hierarchical model can accurately quantify the uncertainty across experiments; improve the posterior probability density function estimation of the parameters, thus, improve predictions on future experiments; identify the most plausible force field to describe the underlying structure of a given dataset. The framework and associated software are applicable to a wide range of nanoscale simulations associated with experimental data with a hierarchical structure.

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UNRES-Dock—protein–protein and peptide–protein docking by coarse-grained replica-exchange MD simulations

Bioinformatics ◽

10.1093/bioinformatics/btaa897 ◽

2020 ◽

Cited By ~ 1

Author(s):

Paweł Krupa ◽

Agnieszka S Karczyńska ◽

Magdalena A Mozolewska ◽

Adam Liwo ◽

Cezary Czaplewski

Keyword(s):

Protein Complexes ◽

Md Simulations ◽

Protein Docking ◽

Conformational Space ◽

Coarse Grained ◽

Supplementary Information ◽

Replica Exchange ◽

Variable Degree ◽

Single Chain ◽

Simulation Speed

Abstract Motivation The majority of the proteins in living organisms occur as homo- or hetero-multimeric structures. Although there are many tools to predict the structures of single-chain proteins or protein complexes with small ligands, peptide–protein and protein–protein docking is more challenging. In this work, we utilized multiplexed replica-exchange molecular dynamics (MREMD) simulations with the physics-based heavily coarse-grained UNRES model, which provides more than a 1000-fold simulation speed-up compared with all-atom approaches to predict structures of protein complexes. Results We present a new protein–protein and peptide–protein docking functionality of the UNRES package, which includes a variable degree of conformational flexibility. UNRES-Dock protocol was tested on a set of 55 complexes with size from 43 to 587 amino-acid residues, showing that structures of the complexes can be predicted with good quality, if the sampling of the conformational space is sufficient, especially for flexible peptide–protein systems. The developed automatized protocol has been implemented in the standalone UNRES package and in the UNRES server. Availability and implementation UNRES server: http://unres-server.chem.ug.edu.pl; UNRES package and data used in testing of UNRES-Dock: http://unres.pl. Supplementary information Supplementary data are available at Bioinformatics online.

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Influence of Calcium Binding on Conformations and Motions of Anionic Polyamino Acids. Effect of Side Chain Length

Polymers ◽

10.3390/polym12061279 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1279

Author(s):

Dmitry Tolmachev ◽

Natalia Lukasheva ◽

George Mamistvalov ◽

Mikko Karttunen

Keyword(s):

Amino Acids ◽

Chain Length ◽

Calcium Binding ◽

Md Simulations ◽

Side Chain ◽

Replica Exchange ◽

Side Chain Length ◽

Hamiltonian Replica Exchange ◽

Cacl2 Concentration ◽

Chain Lengths

Investigation of the effect of CaCl2 salt on conformations of two anionic poly(amino acids) with different side chain lengths, poly-(α-l glutamic acid) (PGA) and poly-(α-l aspartic acid) (PASA), was performed by atomistic molecular dynamics (MD) simulations. The simulations were performed using both unbiased MD and the Hamiltonian replica exchange (HRE) method. The results show that at low CaCl2 concentration adsorption of Ca2+ ions lead to a significant chain size reduction for both PGA and PASA. With the increase in concentration, the chains sizes partially recover due to electrostatic repulsion between the adsorbed Ca2+ ions. Here, the side chain length becomes important. Due to the longer side chain and its ability to distance the charged groups with adsorbed ions from both each other and the backbone, PGA remains longer in the collapsed state as the CaCl2 concentration is increased. The analysis of the distribution of the mineral ions suggests that both poly(amino acids) should induce the formation of mineral with the same structure of the crystal cell.

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Replica exchange MD simulations of two-dimensional water in graphene nanocapillaries: rhombic versus square structures, proton ordering, and phase transitions

Physical Chemistry Chemical Physics ◽

10.1039/c9cp00849g ◽

2019 ◽

Vol 21 (32) ◽

pp. 17640-17654

Author(s):

Shujuan Li ◽

Burkhard Schmidt

Keyword(s):

Phase Transitions ◽

Minimum Energy ◽

Md Simulations ◽

Replica Exchange ◽

Graphene Sheets ◽

Two Dimensional ◽

Proton Ordering

Minimum energy structures of quasi-two dimensional ice confined between graphene sheets.

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Development of a ReaxFF Force Field for Cu/S/C/H and Reactive MD Simulations of Methyl Thiolate Decomposition on Cu (100)

The Journal of Physical Chemistry B ◽

10.1021/acs.jpcb.7b06976 ◽

2017 ◽

Vol 122 (2) ◽

pp. 888-896 ◽

Cited By ~ 9

Author(s):

Jejoon Yeon ◽

Heather L. Adams ◽

Chad E. Junkermeier ◽

Adri C. T. van Duin ◽

Wilfred T. Tysoe ◽

...

Keyword(s):

Force Field ◽

Md Simulations ◽

Reaxff Force Field

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Simulating Absorption Spectra of Flavonoids in Aqueous Solution: A Polarizable QM/MM Study

Molecules ◽

10.3390/molecules25245853 ◽

2020 ◽

Vol 25 (24) ◽

pp. 5853

Author(s):

Sulejman Skoko ◽

Matteo Ambrosetti ◽

Tommaso Giovannini ◽

Chiara Cappelli

Keyword(s):

Molecular Dynamics ◽

Aqueous Solution ◽

Hydrogen Bonding ◽

Force Field ◽

Absorption Spectra ◽

Computational Study ◽

Md Simulations ◽

Quantum Mechanical ◽

Hydrogen Bonding Interactions

We present a detailed computational study of the UV/Vis spectra of four relevant flavonoids in aqueous solution, namely luteolin, kaempferol, quercetin, and myricetin. The absorption spectra are simulated by exploiting a fully polarizable quantum mechanical (QM)/molecular mechanics (MM) model, based on the fluctuating charge (FQ) force field. Such a model is coupled with configurational sampling obtained by performing classical molecular dynamics (MD) simulations. The calculated QM/FQ spectra are compared with the experiments. We show that an accurate reproduction of the UV/Vis spectra of the selected flavonoids can be obtained by appropriately taking into account the role of configurational sampling, polarization, and hydrogen bonding interactions.

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