Molecular Dynamics Simulations of 441 Two-Residue Peptides in Aqueous Solution: Conformational Preferences and Neighboring Residue Effects with the Amber ff99SB-ildn-NMR Force Field

Li, Shuxiang; Andrews, Casey T.; Frembgen-Kesner, Tamara; Miller, Mark S.; Siemonsma, Stephen L.; Collingsworth, Timothy D.; Rockafellow, Isaac T.; Ngo, Nguyet Anh; Campbell, Brady; Brown, Reid F.; Guo, Chengxuan; Schrodt, Michael V.; Liu, Yu-Tsan; Elcock, Adrian H.

doi:10.1021/ct5010966

Cited by 13 publications

(38 citation statements)

References 79 publications

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“…20e Water was modeled explicitly using the TIP4P-Ew model; 24 we selected this model for use in simulations because one of our long-term goals is to study protein-DNA interactions and the combination of the AMBER protein force field with the TIP4P-Ew water model is established as one of the best currently available for modeling peptide systems. 25 Na + and Cl − ions – which were added to 150 mM concentrations in order to crudely mimic physiological concentrations – were modeled using the appropriate set of parameters derived by Joung & Cheatham; 26 for simulations of DNMPs, an additional Na + ion was included to ensure electroneutrality of the system. A view of a typical DNMP system as simulated is shown in Figure S1.…”

Section: Methodsmentioning

confidence: 99%

Stacking Free Energies of All DNA and RNA Nucleoside Pairs and Dinucleoside-Monophosphates Computed Using Recently Revised AMBER Parameters and Compared with Experiment

Brown

Andrews

Elcock

2015

J. Chem. Theory Comput.

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126

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We report the results of a series of 1 μs-long explicit-solvent molecular dynamics (MD) simulations performed to compare the free energies of stacking (ΔGstack) of all possible combinations of DNA and RNA nucleoside (NS) pairs and dinucleoside-monophosphates (DNMPs). For both NS-pairs and DNMPs we show that the computed stacking free energies are in reasonable qualitative agreement with experimental measurements, and appear to provide the closest correspondence with experiment yet found among computational studies; in all cases, however, the computed stacking free energies are too favorable relative to experiment. Comparisons of NS-pair systems indicate that stacking interactions are very similar in RNA and DNA systems except when a thymine or uracil base is involved: the presence of a thymine base favors stacking by ~0.3 kcal/mol relative to a uracil base. One exception is found in the self-stacking of cytidines, which are found to be significantly more favorable for the DNA form; an analysis of the rotational orientations sampled during stacking events suggests that this is likely to be due to more favorable sugar-sugar interactions in stacked complexes of deoxycytidines. Comparisons of the DNMP systems indicate that stacking interactions are more favorable in RNA than in DNA except, again, when thymine or uracil bases are involved. Finally, additional simulations performed using a previous generation of the AMBER force field – in which the description of glycosidic bond rotations was less than optimal – produce computed stacking free energies that are in poorer agreement with experimental data. Overall, the simulations provide a comprehensive view of stacking thermodynamics in NS pairs and in DNMPs as predicted by a state-of-the-art MD force field.

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Section: Methodsmentioning

confidence: 99%

Stacking Free Energies of All DNA and RNA Nucleoside Pairs and Dinucleoside-Monophosphates Computed Using Recently Revised AMBER Parameters and Compared with Experiment

Brown

Andrews

Elcock

2015

J. Chem. Theory Comput.

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126

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“…Nevertheless, for smaller systems – especially short peptides – the present results suggest that a need to recalculate partial charges for the termini might be a potential factor to consider if poor agreement with experimental observables is encountered. 2 …”

Section: Discussionmentioning

confidence: 99%

Osmotic Pressure Simulations of Amino Acids and Peptides Highlight Potential Routes to Protein Force Field Parameterization

2016

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Recent molecular dynamics (MD) simulations of proteins have suggested that common force fields overestimate the strength of amino acid interactions in aqueous solution. In an attempt to determine the causes of these effects, we have measured the osmotic coefficients of a number of amino acids using the AMBER ff99SB-ILDN force field with two popular water models, and compared the results with available experimental data. With TIP4P-Ew water, interactions between aliphatic residues agree well with experiment, but interactions of the polar residues serine and threonine are found to be excessively attractive. For all tested amino acids, the osmotic coefficients are lower when the TIP3P water model is used. Additional simulations performed on charged amino acids indicate that the osmotic coefficients are strongly dependent on the parameters assigned to the salt ions, with a reparameterization of the sodium:carboxylate interaction reported by the Aksimentiev group significantly improving description of the osmotic coefficient for glutamate. For five neutral amino acids, we also demonstrate a decrease in solute-solute attractions using the recently reported TIP4P-D water model and using the KBFF force field. Finally, we show that for four two-residue peptides improved agreement with experiment can be achieved by re-deriving the partial charges for each peptide.

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“…We have derived these additional potential functions by applying the IBI method 38,39 to MD data obtained from 441 two-residue peptides reported in recent work 40 and from a further 45 MD simulations of peptide systems reported here. In all cases, we have found that the IBI procedure enables optimized potential functions to be derived that produce a high level of agreement with the probability distributions obtained from MD (see Figures 2, 3 and S3).…”

Section: Discussionmentioning

confidence: 99%

“…This study takes as its starting point the results of extensive explicit-solvent MD simulations of all combinations of two-residue peptides (441 systems in all) that we reported recently. 40 Here, we describe the derivation and testing of bonded potential functions for backbone pseudoatoms and the additional nonbonded potential functions required to describe the conformational energetics of peptides and proteins. Tests of the extended COFFDROP force field against further MD simulations, and against experimental data on the hydrodynamic radii of intrinsically disordered proteins indicate that the resulting force field is likely to be useful for modeling proteins in a variety of scenarios.…”

Section: Introductionmentioning

confidence: 99%

Parametrization of Backbone Flexibility in a Coarse-Grained Force Field for Proteins (COFFDROP) Derived from All-Atom Explicit-Solvent Molecular Dynamics Simulations of All Possible Two-Residue Peptides

Frembgen-Kesner

Andrews

et al. 2015

J. Chem. Theory Comput.

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Recently, we reported the parameterization of a set of coarse-grained (CG) nonbonded potential functions, derived from all-atom explicit-solvent molecular dynamics (MD) simulations of amino acid pairs, and designed for use in (implicit-solvent) Brownian dynamics (BD) simulations of proteins; this force field was named COFFDROP (COarse-grained Force Field for Dynamic Representations Of Proteins). Here, we describe the extension of COFFDROP to include bonded backbone terms derived from fitting to results of explicit-solvent MD simulations of all possible two-residue peptides containing the 20 standard amino acids, with histidine modeled in both its protonated and neutral forms. The iterative Boltzmann inversion (IBI) method was used to optimize new CG potential functions for backbone-related terms by attempting to reproduce angle, dihedral and distance probability distributions generated by the MD simulations. In a simple test of the transferability of the extended force field, the angle, dihedral and distance probability distributions obtained from BD simulations of 56 three-residue peptides were compared to results from corresponding explicit-solvent MD simulations. In a more challenging test of the COFFDROP force field, it was used to simulate eight intrinsically disordered proteins and was shown to quite accurately reproduce the experimental hydrodynamic radii (Rhydro), provided that the favorable nonbonded interactions of the force field were uniformly scaled downwards in magnitude. Overall, the results indicate that the COFFDROP force field is likely to find use in modeling the conformational behavior of intrinsically disordered proteins and multi-domain proteins connected by flexible linkers.

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Molecular Dynamics Simulations of 441 Two-Residue Peptides in Aqueous Solution: Conformational Preferences and Neighboring Residue Effects with the Amber ff99SB-ildn-NMR Force Field

Cited by 13 publications

References 79 publications

Stacking Free Energies of All DNA and RNA Nucleoside Pairs and Dinucleoside-Monophosphates Computed Using Recently Revised AMBER Parameters and Compared with Experiment

Stacking Free Energies of All DNA and RNA Nucleoside Pairs and Dinucleoside-Monophosphates Computed Using Recently Revised AMBER Parameters and Compared with Experiment

Osmotic Pressure Simulations of Amino Acids and Peptides Highlight Potential Routes to Protein Force Field Parameterization

Parametrization of Backbone Flexibility in a Coarse-Grained Force Field for Proteins (COFFDROP) Derived from All-Atom Explicit-Solvent Molecular Dynamics Simulations of All Possible Two-Residue Peptides

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