On Low-Barrier Hydrogen Bonds and Enzyme Catalysis

Warshel, Arieh; Papazyan, Arno; Kollman, Peter A.

doi:10.1126/science.7661987

Cited by 355 publications

(319 citation statements)

References 23 publications

Supporting

Mentioning

305

Contrasting

Unclassified

Order By: Relevance

“…[21][22][23] Recently, gas-phase single-photon 24 and multiphoton 25 vibrational action spectroscopy experiments and condensed-phase multidimensional infrared experiments 26,27 have become critical in deciphering the precise vibrational signatures that contribute to dynamics in soft-mode hydrogen-bonded systems. In biological systems, many enzymes that catalyze hydrogen-transfer reactions are thought to display tunneling.…”

Section: Introductionmentioning

confidence: 99%

Quantum Wavepacket Ab Initio Molecular Dynamics: An Approach for Computing Dynamically Averaged Vibrational Spectra Including Critical Nuclear Quantum Effects

2007

View full text Add to dashboard Cite

We have introduced a computational methodology to study vibrational spectroscopy in clusters inclusive of critical nuclear quantum effects. This approach is based on the recently developed quantum wavepacket ab initio molecular dynamics method that combines quantum wavepacket dynamics with ab initio molecular dynamics. The computational efficiency of the dynamical procedure is drastically improved (by several orders of magnitude) through the utilization of wavelet-based techniques combined with the previously introduced time-dependent deterministic sampling procedure measure to achieve stable, picosecond length, quantumclassical dynamics of electrons and nuclei in clusters. The dynamical information is employed to construct a novel cumulative flux/velocity correlation function, where the wavepacket flux from the quantized particle is combined with classical nuclear velocities to obtain the vibrational density of states. The approach is demonstrated by computing the vibrational density of states of [Cl-H-Cl] -, inclusive of critical quantum nuclear effects, and our results are in good agreement with experiment. A general hierarchical procedure is also provided, based on electronic structure harmonic frequencies, classical ab initio molecular dynamics, computation of nuclear quantum-mechanical eigenstates, and employing quantum wavepacket ab initio dynamics to understand vibrational spectroscopy in hydrogen-bonded clusters that display large degrees of anharmonicities.

show abstract

Section: Introductionmentioning

confidence: 99%

Quantum Wavepacket Ab Initio Molecular Dynamics: An Approach for Computing Dynamically Averaged Vibrational Spectra Including Critical Nuclear Quantum Effects

2007

View full text Add to dashboard Cite

show abstract

“…In addition, the possible role of VSHBs in enzymatic catalysis broadens their potential significance. [11][12][13][14][15][16][17][18] The purpose of this present paper is to enlighten on some structural and dynamical features of these bonds.…”

Section: Introductionmentioning

confidence: 99%

A neutron scattering study of strong-symmetric hydrogen bonds in potassium and cesium hydrogen bistrifluoroacetates: Determination of the crystal structures and of the single-well potentials for protons

Cousson

Archilla

Tomkinson

2008

The Journal of Chemical Physics

View full text Add to dashboard Cite

The crystal structures of potassium and cesium bistrifluoroacetates, KH͑CF 3 COO͒ 2 and CsH͑CF 3 COO͒ 2 , respectively, were determined at room and cryogenic temperatures with the single crystal neutron diffraction technique. The crystals belong to the monoclinic space groups, I2 / a and A2 / a, respectively, and there is no evidence of any structural phase transition. In both crystals, trifluoroacetate entities in centrosymmetric dimers are linked by very short hydrogen bonds lying across a center of inversion. The thermal parameters provide no evidence of any double minimum potential for hydrogen bond protons. Single-minimum potentials were determined via best fitting to the inelastic neutron scattering spectral profiles of the stretching vibrations. They comprise a narrow well for the ground state and a very broad quasiharmonic well for excited states. The spread out of the wave functions of these states shows that protons are no longer confined between the oxygens. Presumably, they are attracted by the lone pairs of oxygen atoms. These potentials emphasize the covalent nature of the OO bond and the ionic character of the hydrogen bond proton.

show abstract

“…Simulations have played a significant role in establishing the impor-tance of electrostatic interactions for enzyme function, especially for the catalytic steps (37)(38)(39)(40)(41)(42)(43). Whereas the general concepts are well understood today (see Ref.…”

mentioning

confidence: 99%

Ammonium Scanning in an Enzyme Active Site

Thompson

Lazennec

Plateau

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

The aminoacyl-tRNA synthetases (aaRSs) 3 play a crucial role in preserving the accuracy of genetic code translation, linking each amino acid to a cognate tRNA, which carries the corresponding anticodon. Each of the 20 aaRSs must bind its target amino acid substrate with a high specificity (1-8). In the "class IIb" subgroup, formed of AspRS (9 -16, 21-26), AsnRS (17,24),25), a network of electrostatic interactions ensures binding specificity for the cognate amino acid side chain in each case. Experimental and theoretical studies show, for example, that the preference of AspRS for Asp over its neutral analogue, Asn, involves a complex mechanism (24, 25). Proton binding, ATP binding, and long-range electrostatic interactions play important roles, and net positive electrostatic potential in the active site permits AspRS to bind L-Asp much more strongly than L-Asn.The translation apparatus must also preserve the homochirality of proteins, and aaRSs should be specific for L-amino acids. Kinetic experiments show, however, that AspRS does not strongly distinguish between the "left-handed" L-Asp and "right-handed" D-Asp stereoisomers. Indeed, D-Asp-tRNA Asp is produced at detectable levels by Escherichia coli AspRS (26), at a rate only 4,000 times lower than L-Asp-tRNA Asp . To preserve homochirality in vivo (27), editing (28) of D-Asp-tRNA Asp by a D-aminoacyl-tRNA deacylase is performed (26). For biotechnology applications, it is not always desirable to preserve homochirality, and D-amino acids are of great potential interest in protein engineering and design. For example, mixed L-and D-amino acid proteins are used in the development of synthetic vaccines (29,30). It is hence of interest, both from a fundamental and an engineering perspective, to better understand how aaRSs distinguish between L-and D-amino acids.In the present work, we use simulations and experiments to investigate the origins of chiral specificity of E. coli AspRS for its L-aspartate substrate (L-Asp). Asp has a pseudosymmetry, broken only by its ammonium group, and so the enzyme must protect not only against D-Asp, but against an alternate, "inverted" orientation where the two substrate carboxylates are swapped (Fig. 1A). The inverted orientation is seen in the crystal structure of a homologous enzyme, asparagine synthetase (31). We compare both L-Asp and D-Asp, in regular and inverted orientations, and the metabolite succinate, where the ammonium group is removed altogether and the ligand has an additional negative charge. This is done with a state of the art molecular dynamics free energy (MDFE) technique (21)(22)(23)(24)(25)(32)(33)(34)(35)(36)(37)(38)(39), by computing the change in binding free energy when an ammonium group is inserted at either possible position on either succinate methylene group.By scanning all possible ammonium positions on the ligand, we can also address an interesting, secondary question: the strength of electrostatic interactions in the active site. Simulations have played a significant role in establishing the impor-

show abstract

On Low-Barrier Hydrogen Bonds and Enzyme Catalysis

Cited by 355 publications

References 23 publications

Quantum Wavepacket Ab Initio Molecular Dynamics: An Approach for Computing Dynamically Averaged Vibrational Spectra Including Critical Nuclear Quantum Effects

Quantum Wavepacket Ab Initio Molecular Dynamics: An Approach for Computing Dynamically Averaged Vibrational Spectra Including Critical Nuclear Quantum Effects

A neutron scattering study of strong-symmetric hydrogen bonds in potassium and cesium hydrogen bistrifluoroacetates: Determination of the crystal structures and of the single-well potentials for protons

Ammonium Scanning in an Enzyme Active Site

Contact Info

Product

Resources

About