A combined NMR/MD/QM approach for structure and dynamics elucidations in the solution state: pilot studies using tetrapeptides

Aliev, Abil E.; Courtier‐Murias, Denis; Bhandal, Simrath; Zhou, Shen

doi:10.1039/b910499b

Cited by 13 publications

(34 citation statements)

References 14 publications

(7 reference statements)

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“…Conformations in (a)-(d) are similar to those from the HF/cc-pVDZ geometry optimizations using the IEFPCM solvation model for water, initial structures for which were extracted from the MD OPLS-AA/L TIP4P simulation. 1 For MD simulations of GPGG using different force fields the distribution of various backbone conformations is best illustrated by histograms of d ter , as predicted by 2 µs long MD simulations using different force fields. From the distribution curves shown in Figure 3, it is apparent that significantly different populations of backbone conformations are predicted by different force fields; i.e., some of them predict the preference of the folded backbone, whereas others give preference to the unfolded backbone conformation.…”

Section: Force Field Dependence Of MD Resultsmentioning

confidence: 99%

“…1 Among the three techniques used, the choice of the suitable protocol is most ambiguous at the MD stage of analysis compared to either QM methods or NMR. In particular, the choice of the force field is of primary concern, as there are many different force fields, optimized using either experimental or quantum mechanical data or a combination of both.…”

Section: Introductionmentioning

confidence: 99%

“…With these considerations in mind, we have compared the performance of 12 different GROMOS, 21,22 AMBER, [23][24][25][26][27][28][29][30] OPLS-AA, 31,32 and CHARMM 33,34 force fields for simulations 1 H decoupling, as well as two-dimensional selective heteronuclear J-resolved and J-HMBC spectra were used for the measurements of vicinal 1 H-13 C couplings. 42, 43 Uncertainties in measured values of J-couplings and 1 H chemical shift differences were less than (0.1 Hz.…”

Section: Introductionmentioning

confidence: 99%

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Experimental Verification of Force Fields for Molecular Dynamics Simulations Using Gly-Pro-Gly-Gly

Aliev

Courtier‐Murias

2010

J. Phys. Chem. B

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Experimental NMR verification of MD simulations using 12 different force fields (AMBER, CHARMM, GROMOS, and OPLS-AA) and 5 different water models has been undertaken to identify reliable MD protocols for structure and dynamics elucidations of small open chain peptides containing Gly and Pro. A conformationally flexible tetrapeptide Gly-Pro-Gly-Gly was selected for NMR (3)J-coupling, chemical shift, and internuclear distance measurements, followed by their calculations using 2 μs long MD simulations in water. In addition, Ramachandran population maps for Pro-2 and Gly-3 residues of GPGG obtained from MD simulations were used for detailed comparisons with similar maps from the protein data bank (PDB) for large number of Gly and Pro residues in proteins. The MD simulations revealed strong dependence of the populations and geometries of preferred backbone and side chain conformations, as well as the time scales of the peptide torsional transitions on the force field used. On the basis of the analysis of the measured and calculated data, AMBER99SB is identified as the most reliable force field for reproducing NMR measured parameters, which are dependent on the peptide backbone and the Pro side chain geometries and dynamics. Ramachandran maps showing the dependence of conformational populations as a function of backbone ϕ/ψ angles for Pro-2 and Gly-3 residues of GPGG from MD simulations using AMBER99SB, AMBER03, and CHARMM were found to resemble similar maps for Gly and Pro residues from the PDB survey. Three force fields (AMBER99, AMBER99ϕ, and AMBER94) showed the least satisfactory agreement with both the solution NMR and the PDB survey data. The poor performance of these force fields is attributed to their propensity to overstabilize helical peptide backbone conformations at the Pro-2 and Gly-3 residues. On the basis of the similarity of the MD and PDB Ramachandran plots, the following sequence of transitions is suggested for the Gly backbone conformation: α(L) ⇆ β(PR) ⇆ β(S) ⇆ β(P) ⇆ α, where backbone secondary structures α(L) and α are associated with helices and turns, β(P) and β(PR) correspond to the left- and right-handed polyproline II structures and β(S) denotes the fully stretched backbone conformation. Compared to the force field dependence, less significant, but noteworthy, variations in the populations of the peptide backbone conformations were observed. For different solvent models considered, a correlation was noted between the number of torsional transitions in GPGG and the water self-diffusion coefficient on using TIP3P, TIP4P, and TIP5P models. In addition to MD results, we also report DFT derived Karplus relationships for Gly and Pro residues using B972 and B3LYP functionals.

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Section: Force Field Dependence Of MD Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Experimental Verification of Force Fields for Molecular Dynamics Simulations Using Gly-Pro-Gly-Gly

Aliev

Courtier‐Murias

2010

J. Phys. Chem. B

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“…The synthesis of AHM and AHG is described in Supporting Infromation. Experimental values of proton 3 J HH couplings and internuclear proton distances for N -acetyl- l -proline (NAcPro), Gly-Pro-Gly-Gly (GPGG) and Val-Ala-Pro-Gly (VAPG) in D 2 O solutions at 298 K were taken from Refs 34–36…”

Section: Methodsmentioning

confidence: 99%

“…Unless otherwise specified, the trans -orientation about the amide bond preceding the Pro (or Hyp) residue is assumed for a given peptide. For the values of 3 J -couplings determined from the full lineshape analysis, the standard deviation was estimated to be <0.1 Hz 34–36. Experimental values of 3 J -couplings for ubiquitin were taken from Refs 37.…”

Section: Methodsmentioning

confidence: 99%

Motional timescale predictions by molecular dynamics simulations: Case study using proline and hydroxyproline sidechain dynamics

et al. 2013

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We propose a new approach for force field optimizations which aims at reproducing dynamics characteristics using biomolecular MD simulations, in addition to improved prediction of motionally averaged structural properties available from experiment. As the source of experimental data for dynamics fittings, we use 13C NMR spin-lattice relaxation times T1 of backbone and sidechain carbons, which allow to determine correlation times of both overall molecular and intramolecular motions. For structural fittings, we use motionally averaged experimental values of NMR J couplings. The proline residue and its derivative 4-hydroxyproline with relatively simple cyclic structure and sidechain dynamics were chosen for the assessment of the new approach in this work. Initially, grid search and simplexed MD simulations identified large number of parameter sets which fit equally well experimental J couplings. Using the Arrhenius-type relationship between the force constant and the correlation time, the available MD data for a series of parameter sets were analyzed to predict the value of the force constant that best reproduces experimental timescale of the sidechain dynamics. Verification of the new force-field (termed as AMBER99SB-ILDNP) against NMR J couplings and correlation times showed consistent and significant improvements compared to the original force field in reproducing both structural and dynamics properties. The results suggest that matching experimental timescales of motions together with motionally averaged characteristics is the valid approach for force field parameter optimization. Such a comprehensive approach is not restricted to cyclic residues and can be extended to other amino acid residues, as well as to the backbone. Proteins 2014; 82:195–215. © 2013 Wiley Periodicals, Inc.

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Water scaffolding in collagen: Implications on protein dynamics as revealed by solid‐state NMR

Aliev

Courtier‐Murias

2013

Biopolymers

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A combined NMR/MD/QM approach for structure and dynamics elucidations in the solution state: pilot studies using tetrapeptides

Abstract: A combined experimental-computational method is reported for structure and dynamics elucidations of highly flexible open chain molecules in the solution state.

Cited by 13 publications

References 14 publications

Experimental Verification of Force Fields for Molecular Dynamics Simulations Using Gly-Pro-Gly-Gly

Experimental Verification of Force Fields for Molecular Dynamics Simulations Using Gly-Pro-Gly-Gly

Motional timescale predictions by molecular dynamics simulations: Case study using proline and hydroxyproline sidechain dynamics

Water scaffolding in collagen: Implications on protein dynamics as revealed by solid‐state NMR

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