Validation of molecular simulation by comparison with experiment: Rotational reorientation of tryptophan in water

Daura, Xavier; Suter, Rafael; Gunsteren, Wilfred F. van

doi:10.1063/1.477900

Cited by 38 publications

(50 citation statements)

References 19 publications

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“…Formation of native-like structures is determined through rmsd relative to the experimental GCAA tetraloop, and clustering analysis is used to determine the statistical prevalence of the different configurations. The rmsd of structures in multiple temperature ensembles is compared with the NMR structure [Protein Data Bank ID code 1ZIH] (55) and subsequently clustered using a 1-Å cutoff using the single-linkage clustering method and the method by Daura et al (56) (pairwise rmsd of all structures).…”

Section: Methodsmentioning

confidence: 99%

Free-energy landscape of a hyperstable RNA tetraloop

Miner

Chen

Garcı́a

2016

Proc. Natl. Acad. Sci. U.S.A.

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We report the characterization of the energy landscape and the folding/unfolding thermodynamics of a hyperstable RNA tetraloop obtained through high-performance molecular dynamics simulations at microsecond timescales. Sampling of the configurational landscape is conducted using temperature replica exchange molecular dynamics over three isochores at high, ambient, and negative pressures to determine the thermodynamic stability and the freeenergy landscape of the tetraloop. The simulations reveal reversible folding/unfolding transitions of the tetraloop into the canonical A-RNA conformation and the presence of two alternative configurations, including a left-handed Z-RNA conformation and a compact purine Triplet. Increasing hydrostatic pressure shows a stabilizing effect on the A-RNA conformation and a destabilization of the lefthanded Z-RNA. Our results provide a comprehensive description of the folded free-energy landscape of a hyperstable RNA tetraloop and highlight the significant advances of all-atom molecular dynamics in describing the unbiased folding of a simple RNA secondary structure motif.RNA | free-energy landscape | molecular dynamics | tetraloop | pressure T he stability of a folded RNA molecule depends on a complex set of interactions between the RNA with itself and the surrounding environment. Secondary RNA structures fold by a combination of complimentary base pairing, nucleotide stacking, and screening of the anionic phosphate backbone (1), but these interactions depend heavily on the local solution environment, and the RNA configuration can be either stabilized or destabilized by a number of extrinsic factors, including temperature (2), pressure (3), denaturants, and salt concentration (4). Even in simple RNA duplexes, changes in pressure and ion concentrations have been shown to drive the formation of alternative configurations (5, 6) and change the RNA folded ensemble. Characterizing the effects that these different factors have on the folded free-energy landscape of RNA is crucial for determining the thermodynamic stability of different RNA motifs and the probability of transitions between configurations.Small RNA hairpins have been used as a model system for characterizing RNA folding and stability for decades because of their small size, their ubiquitous presence in many natural systems, and the complexity of their internal interactions (7-11). Hairpins result when a single oligonucleotide strand bends 180°t o form an antiparallel duplex through complementary base pairing. The bent, single-stranded loop region is capable of forming complex hydrogen bond networks (12) or long-range interactions with other RNAs (13). Some of the most thermodynamically stable RNA hairpins form loop regions of 4 nt, called tetraloops (14), which are highly compact, structurally conserved, and typically stabilized by the formation of a network of hydrogen bonds (15) that decrease the loop conformational entropy.These tetraloop structures have been explored through multiple experimental (16-23) and computational...

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Section: Methodsmentioning

confidence: 99%

Free-energy landscape of a hyperstable RNA tetraloop

Miner

Chen

Garcı́a

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…1,[5][6][7][8] The conformational space of a single tryptophan in water was studied by different NMR techniques, 3 and six low-energy conformations were obtained. One major conformation, the g -conformation with the ring in an orientation perpendicular to the C R -C bond, 9 was calculated to contain about 70% of all conformations.…”

Section: Introductionmentioning

confidence: 99%

A Molecular Dynamics Study of Tryptophan in Water

Mark

Nilsson

2002

J. Phys. Chem. B

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Molecular dynamics simulations of a single tryptophan amino acid in water were performed with the CHARMM molecular mechanics program using the modified TIP3P, the refined SPC, and the original SPC/E water models. All these empirical water models are similar in nature, but small differences give significant differences in their properties for liquid water. Nanosecond molecular dynamics simulations were carried out in the NVT, NVE, or NPT ensembles using a cubic simulation cell furnished with periodic boundary conditions. The calculations of long-range interactions were performed with two different methods, the atom-based spherical cutoff method with force shifting, where the nonbonded interactions were smoothly shifted to zero at the cutoff distance, and the particle-mesh Ewald technique. Transition dipole autocorrelation functions and reorientation times of tryptophan were calculated and compared to experimental values. Tryptophan hydration was affected by the water model and the treatment of long-range electrostatic interactions. The reorientation time of tryptophan depended strongly on the water model used, and the viscosity of the model liquid was found to correlate with the tryptophan translational and rotational dynamics in water. Statistical accuracy and errors in the analyses are discussed.

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“…For the GROMOS96 force field, the best agreement with experiment was obtained with the SPC/E water model in conjunction with a reaction field correction for the long-range electrostatic interactions [115].…”

Section: Fluorescence Anisotropy Decaymentioning

confidence: 99%

How Do Rotameric Conformations Influence the Time-Resolved Fluorescence of Tryptophan in Proteins? A Perspective Based on Molecular Modeling and Quantum Chemistry

Moors¹,

Jonckheer²,

Maeyer³

et al. 2008

CPPS

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We discuss the dynamics of tryptophan rotamers in the context of the non-exponential fluorescence decay in proteins. The central question is: how does the ground-state conformational heterogeneity influence the time evolution of tryptophan fluorescence? This problem is examined here from the theoretical perspective. Three methods at different levels of theory, and with different scopes and computational requirements are reviewed. The Dead-end elimination method is limited to side-chain dynamics and provides an efficient way to detect the stable tryptophan rotamers in a protein. Its application to the study of heterogeneous emission characteristics is illustrated. Molecular dynamics is aimed at the full phase space of the macromolecule in solution, but must rely on classical force fields and laws of evolution. We examine to what extent the molecular mechanics paradigm yields sufficiently accurate thermodynamic results, and what are the possible kinetic implications. Finally Quantum Chemistry is the only theoretical method that allows a direct assessment of the excited states. It is necessarily restricted to small molecular systems, and thus must be used in a hybrid combination with classical methods and electrostatic models. So far understanding of the emitting state has greatly progressed as a result of these calculations, but the actual treatment of the photophysical decay processes at the quantum level has not yet really started.

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Validation of molecular simulation by comparison with experiment: Rotational reorientation of tryptophan in water

Cited by 38 publications

References 19 publications

Free-energy landscape of a hyperstable RNA tetraloop

Free-energy landscape of a hyperstable RNA tetraloop

A Molecular Dynamics Study of Tryptophan in Water

How Do Rotameric Conformations Influence the Time-Resolved Fluorescence of Tryptophan in Proteins? A Perspective Based on Molecular Modeling and Quantum Chemistry

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