How Accurately Do Current Force Fields Predict Experimental Peptide Conformations? An Adiabatic Free Energy Dynamics Study

2014 ◽  
Vol 118 (24) ◽  
pp. 6539-6552 ◽  
Author(s):  
Alexandar T. Tzanov ◽  
Michel A. Cuendet ◽  
Mark E. Tuckerman
Keyword(s):  
Free Energy ◽  
Force Fields ◽  
Energy Dynamics ◽  
Peptide Conformations

Thermodynamics of Helix formation in small peptides of varying lengthin vacuo, implicit solvent and explicit solvent: Comparison between AMBER force fields

2019 ◽  
Vol 18 (03) ◽  
pp. 1950015
Author(s):  
Zhaoxi Sun ◽  
Xiaohui Wang
Keyword(s):  
Amino Acids ◽  
Free Energy ◽  
Hydrogen Bonds ◽  
Force Fields ◽  
Implicit Solvent ◽  
Conformational Ensemble ◽  
Helix Formation ◽  
Solvent Models ◽  
Explicit Solvent ◽  
Amber Force Fields

Helix formation is of great significance in protein folding. The helix-forming tendencies of amino acids are accumulated along the sequence to determine the helix-forming tendency of peptides. Computer simulation can be used to model this process in atomic details and give structural insights. In the current work, we employ equilibrate-state free energy simulation to systematically study the folding/unfolding thermodynamics of a series of mutated peptides. Two AMBER force fields including AMBER99SB and AMBER14SB are compared. The new 14SB force field uses refitted torsion parameters compared with 99SB and they share the same atomic charge scheme. We find that in vacuo the helix formation is mutation dependent, which reflects the different helix propensities of different amino acids. In general, there are helix formers, helix indifferent groups and helix breakers. The helical structure becomes more favored when the length of the sequence becomes longer, which arises from the formation of additional backbone hydrogen bonds in the lengthened sequence. Therefore, the helix indifferent groups and helix breakers will become helix formers in long sequences. Also, protonation-dependent helix formation is observed for ionizable groups. In 14SB, the helical structures are more stable than in 99SB and differences can be observed in their grouping schemes, especially in the helix indifferent group. In solvents, all mutations are helix indifferent due to protein–solvent interactions. The decrease in the number of backbone hydrogen bonds is the same with the increase in the number of protein–water hydrogen bonds. The 14SB in explicit solvent is able to capture the free energy minima in the helical state while 14SB in implicit solvent, 99SB in explicit solvent and 99SB in implicit solvent cannot. The helix propensities calculated under 14SB agree with the corresponding experimental values, while the 99SB results obviously deviate from the references. Hence, implicit solvent models are unable to correctly describe the thermodynamics even for the simple helix formation in isolated peptides. Well-developed force fields and explicit solvents are needed to correctly describe the protein dynamics. Aside from the free energy, differences in conformational ensemble under different force fields in different solvent models are observed. The numbers of hydrogen bonds formed under different force fields agree and they are mostly determined by the solvent model.

Computational model of excitable cell indicates ATP free energy dynamics in response to calcium oscillations are undampened by cytosolic ATP buffers

2006 ◽  
Vol 153 (5) ◽  
pp. 405 ◽  
Author(s):  
R.G.P.M. van Stiphout ◽  
N.A.W. van Riel ◽  
P.J. Verhoog ◽  
P.A.J. Hilbers ◽  
K. Nicolay ◽  
...  
Keyword(s):  
Free Energy ◽  
Computational Model ◽  
Calcium Oscillations ◽  
Excitable Cell ◽  
Energy Dynamics

scholarly journals A Simple Method for Including Polarization Effects in Solvation Free Energy Calculations When Using Fixed-Charge Force Fields: Alchemically Polarized Charges.

2020 ◽  
Author(s):  
Braden Kelly ◽  
William Smith
Keyword(s):  
Free Energy ◽  
Electronic Structure ◽  
Force Fields ◽  
Free Energy Calculations ◽  
Fixed Charge ◽  
Basis Sets ◽  
Hydration Free Energy ◽  
Simple Method ◽  
Test Set ◽  
Partial Charges

<div><div>The incorporation of polarizability in classical force-field molecular simulations is an ongoing area of research. We focus here on its application to hydration free energy simulations of organic molecules. In contrast to computationally complex approaches involving the development of explicitly polarizable force fields, we present herein a simple methodology for incorporating polarization into such simulations using standard fixed-charge force-fields, which we call the Alchemically Polarized Charges (APolQ) method. APolQ employs a standard classical alchemical free energy change simulation to calculate the free energy difference between a fully polarized solute particle in a condensed phase and its unpolarized state in a vacuum. One electronic structure (ES) calculation to of the electron densities is required for each state: for the former, we use a Polarizable Continuum Model (PCM), and for the latter we use vacuum-phase electronic structure calculations.</div><div><br></div><div>We applied APolQ to hydration free energy data for a test set of 45 neutral solute molecules in the FreeSolv database, and compared results obtained using three different water models (SPC/E, TIP3P, OPC3) and using MBIS and RESP partial charge methodologies. ES calculations were carried out at the MP2 level of theory and with cc-pVTZ and aug-cc-pVTZ basis sets. In comparison with AM1-BCC, we found that APolQ outperforms it for the test set. Despite our method using default GAFF parameters, the MBIS partial charges yield Absolute Average Deviations (AAD) 1.5 to 1.9 kJ·mol<sup>−1</sup> lower than AM1-BCC.</div><div><br></div><div>We conjecture that this method can be further improved by fitting the Lennard-Jones and torsional parameters to partial charges derived using MBIS or RESP methodologies. </div></div>

Aqueous ionic liquids and their influence on peptide conformations: denaturation and dehydration mechanisms

2017 ◽  
Vol 19 (31) ◽  
pp. 20430-20440 ◽  
Author(s):  
Diddo Diddens ◽  
Volker Lesch ◽  
Andreas Heuer ◽  
Jens Smiatek
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Ionic Liquids ◽  
Molecular Dynamics Simulations ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
Peptide Conformations ◽  
Dynamics Simulations

The influence of different aqueous ionic liquids on peptide conformations is studied by a combination of atomistic molecular dynamics simulations, Kirkwood–Buff theory and free energy calculations.

scholarly journals Effects of Water Models on Binding Affinity: Evidence from All-Atom Simulation of Binding of Tamiflu to A/H5N1 Neuraminidase

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Trang Truc Nguyen ◽  
Man Hoang Viet ◽  
Mai Suan Li
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Binding Affinity ◽  
Force Fields ◽  
Binding Free Energy ◽  
Molecular Mechanic ◽  
Water Density ◽  
Wild Type ◽  
Oseltamivir Carboxylate ◽  
Water Models

The influence of water models SPC, SPC/E, TIP3P, and TIP4P on ligand binding affinity is examined by calculating the binding free energyΔGbindof oseltamivir carboxylate (Tamiflu) to the wild type of glycoprotein neuraminidase from the pandemic A/H5N1 virus.ΔGbindis estimated by the Molecular Mechanic-Poisson Boltzmann Surface Area method and all-atom simulations with different combinations of these aqueous models and four force fields AMBER99SB, CHARMM27, GROMOS96 43a1, and OPLS-AA/L. It is shown that there is no correlation between the binding free energy and the water density in the binding pocket in CHARMM. However, for three remaining force fieldsΔGbinddecays with increase of water density. SPC/E provides the lowest binding free energy for any force field, while the water effect is the most pronounced in CHARMM. In agreement with the popular GROMACS recommendation, the binding score obtained by combinations of AMBER-TIP3P, OPLS-TIP4P, and GROMOS-SPC is the most relevant to the experiments. For wild-type neuraminidase we have found that SPC is more suitable for CHARMM than TIP3P recommended by GROMACS for studying ligand binding. However, our study for three of its mutants reveals that TIP3P is presumably the best choice for CHARMM.

scholarly journals Accurate force fields and methods for modelling organic molecular crystals at finite temperatures

2016 ◽  
Vol 18 (23) ◽  
pp. 15828-15837 ◽  
Author(s):  
Jonas Nyman ◽  
Orla Sheehan Pundyke ◽  
Graeme M. Day
Keyword(s):  
Free Energy ◽  
Force Fields ◽  
Molecular Crystals ◽  
Lattice Energy ◽  
Organic Crystals ◽  
Organic Molecular Crystals ◽  
Energy Modelling

We assess a series of atom–atom force fields for lattice energy and free energy modelling of molecular organic crystals.

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