Structure and activity of the tyrosy1-tRNA synthetase: the hydrogen bond in catalysis and specificity

The role ofhydrogen bonding in specificity, binding and catalysis by the tyrosyl-tRNA synthetase from Bacillus stearothermophilus has been investigated by systematic mutation of residues which form hydrogen bonds with substrates during the reaction between ATP and tyrosine to form tyrosyl adenylate. Data on hydrogen bonding as a determinant of biological specificity are summarized thus: deletion of an hydrogen-bond donor or acceptor between the enzyme and substrate to leave an unpaired but uncharged acceptor or donor weakens binding by only 2-7 kJ mol -1 ; but deletion to leave an unpaired but charged acceptor or donor weakens binding by some 17 kJ mol -1 or so. Hydrogen bonding is found to have a profound role in catalysis by mediating the differential binding of substrates, transition states and products. The formation of tyrosyl adenylate is not catalysed by classical mechanisms of acid-base or nucleophilic catalysis but the enhancement of rate is solely a result of a combination ofhydrogen bonding and electrostatic interactions which stabilize the transition state of the substrates relative to their ground states. The binding energy of ATP increases by more than 29 kJ mol -1 as it passes through the transition state, enhancing the rate by more than a factor of 10 5 . The residues involved in differential binding are spread over the molecule, away from the seat of reaction. The catalysis is delocalized over the whole binding site and not restricted to one or two specific residues. Some regions of the binding site are complementary in structure to the intermediate, tyrosyl adenylate. The apparent binding energies of certain side chains increase as the reaction proceeds, being weakest in the enzyme—substrate complex, stronger in the enzyme-transition-state complex and strongest in the enzyme-intermediate complex. This converts the unfavourable equilibrium constant for the formation of tyrosyl adenylate in solution to a favourable value for the enzyme-bound reagents and helps sequester the reactive tyrosyl adenylate.

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Faculty Opinions recommendation of Selective stabilization of the chorismate mutase transition state by a positively charged hydrogen bond donor.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1012843.187412 ◽

2003 ◽

Author(s):

Arieh Warshel

Keyword(s):

Hydrogen Bond ◽

Transition State ◽

Chorismate Mutase ◽

Hydrogen Bond Donor ◽

Selective Stabilization ◽

Positively Charged

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Machine learning models for hydrogen bond donor and acceptor strengths using large and diverse training data generated by first-principles interaction free energies

Journal of Cheminformatics ◽

10.1186/s13321-019-0381-4 ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 3

Author(s):

Christoph A. Bauer ◽

Gisbert Schneider ◽

Andreas H. Göller

Keyword(s):

Machine Learning ◽

Hydrogen Bond ◽

Hydrogen Bonding ◽

Training Data ◽

Free Energies ◽

Hydrogen Bond Donor ◽

Chemical Application ◽

Hydrogen Bond Acceptor ◽

Donor And Acceptor ◽

Target Values

Abstract We present machine learning (ML) models for hydrogen bond acceptor (HBA) and hydrogen bond donor (HBD) strengths. Quantum chemical (QC) free energies in solution for 1:1 hydrogen-bonded complex formation to the reference molecules 4-fluorophenol and acetone serve as our target values. Our acceptor and donor databases are the largest on record with 4426 and 1036 data points, respectively. After scanning over radial atomic descriptors and ML methods, our final trained HBA and HBD ML models achieve RMSEs of 3.8 kJ mol−1 (acceptors), and 2.3 kJ mol−1 (donors) on experimental test sets, respectively. This performance is comparable with previous models that are trained on experimental hydrogen bonding free energies, indicating that molecular QC data can serve as substitute for experiment. The potential ramifications thereof could lead to a full replacement of wetlab chemistry for HBA/HBD strength determination by QC. As a possible chemical application of our ML models, we highlight our predicted HBA and HBD strengths as possible descriptors in two case studies on trends in intramolecular hydrogen bonding.

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Selective encapsulation and extraction of hydrogenphosphate by a hydrogen bond donor tripodal receptor

CrystEngComm ◽

10.1039/d0ce00834f ◽

2020 ◽

Vol 22 (37) ◽

pp. 6152-6160

Author(s):

Sandeep Kumar Dey ◽

Archana ◽

Sybil Pereira ◽

Sarvesh S. Harmalkar ◽

Shashank N. Mhaldar ◽

...

Keyword(s):

Hydrogen Bond ◽

Hydrogen Bonding ◽

Hydrogen Bonds ◽

Hydrogen Bond Donor ◽

Tripodal Receptor ◽

Multiple Hydrogen Bonds

Intramolecular N–H⋯OC hydrogen bonding between the inner amide groups dictates the receptor–anion complementarity in a tripodal receptor towards selective encapsulation of hydrogenphosphate in the outer urea cavity by multiple hydrogen bonds.

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Polysulfonylamine, CXXVI [1] Wasserstoffbrücken in kristallinen Onium-dimesylamiden: Ein robustes Achtring-Synthon in Koexistenz mit einem dritten Wasserstoffbrückenmotiv - Cyclodimere, Ketten, supramolekulare Bindungsisomere und ein fünffach verwobenes dreidimensionales (C-H ∙∙∙ O - Netzwerk / Polysulfonylamines, CXXVI [1] Hydrogen Bonding in Crystalline Onium Dimesylamides: A Robust Eight- Membered Ring Synthon in Coexistence with a Third Hydrogen Bonding Motif - Cyclodimers, Chains, Supramolecular Linkage Isomers, and a Quintuply Interwoven Three-Dimensional C - H ∙∙∙ O Network

Zeitschrift für Naturforschung B ◽

10.1515/znb-2000-0812 ◽

2000 ◽

Vol 55 (8) ◽

pp. 738-752 ◽

Cited By ~ 4

Author(s):

Oliver Moers ◽

Karna Wijaya ◽

Ilona Lange ◽

Armand Blaschette ◽

Peter G. Jones

Keyword(s):

Hydrogen Bond ◽

Hydrogen Bonding ◽

Crystal Engineering ◽

Ion Pairs ◽

Three Dimensional ◽

Membered Ring ◽

Monoclinic Space Group ◽

Hydrogen Bond Donor ◽

Linkage Isomers ◽

Ionic Solids

As an exercise in crystal engineering, low-temperature X-ray structures were determined for six rationally designed ionic solids of general formula BH+(MeSO2)2N−, where BH+ is 2-aminopyridinium (2, monoclinic, space group P21/c, Z = 4), 2-aminopyrimidinium (3, orthorhombic, Pbca, Z = 8), 2-aminothiazolium (4, orthorhombic, Pbcn, Z = 8), 2-amino-6-methylpyridinium (5, solvated with 0.5 H20, monoclinic, C2/c, Z = 8), 2-amino-1,3,4-thiadiazolium (6, triclinic, P1̄, Z = 2), or 2-amino-4,6-dimethylpyrimidinium (7, orthorhombic. Fdd2, Z = 16). The onium cations in question exhibit a trifunctional hydrogen-bond donor sequence H − N (H*)-C (sp2) − N − H , which is complementary to an O − S (sp3)−N fragment of the anion and simultaneously expected to form a third hydrogen bond via the exocyclic N − H* donor. Consequently, all the crystal packings contain cation-anion pairs assembled by an N − H ∙∙∙ N and an N −H ∙∙∙ O hydrogen bond, these substructures being mutually associated through an N − H* ∙∙∙ O bond. For the robust eight-membered ring synthon within the ion pairs [graph set N2 = R22(8), antidromic], two supramolecular isomers were observed: In 2 and 3, N − H ∙∙∙ N originates from the ring NH donor and N − H ∙∙∙ O from the exocyclic amino group, whereas in 4-7 these connectivities are reversed. The third hydrogen bond, N − H*∙∙∙ O , leads either to chains of ion pairs (generated by a 21 transformation in 2-4 or by a glide plane in 5) or to cyclic dimers of ion pairs (Ci symmetric in 6, C2-symmetric in 7). The overall variety of motifs observed in a small number of structures reflects the limits imposed on the prediction of hydrogen bonding patterns. Owing to the excess of potential acceptors over traditional hydrogen-bond donors, several of the structures display prominent non-classical secondary bonding. Thus, the cyclodimeric units of 6 are associated into strands through short antiparallel O ∙∙∙ S(cation) interactions. In the hemihydrate 5, two independent C-H(cation) ∙∙∙ O bonds generate a second antidromic R22(8) pattern, leading to sheets composed of N − H ∙∙∙ N/O connected catemers; the water molecules are alternately sandwiched between and O - H ∙∙∙ O bonded to the sheets to form bilayers, which are cross-linked by a third C − H (cation ) ∙∙∙ O contact. The roof-shaped cyclodimers occurring in 7 occupy the polar C2 axes parallel to z and build up hollow Car− H ∙∙∙ O bonded tetrahedral lattices; in order to fill their large empty cavities, five translationally equivalent lattices mutually interpenetrate.

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Hydrogen-bond patterns in 1,4-dihydro-2,3-quinoxalinediones: ligands for the glycine modulatory site on the NMDA receptor

Acta Crystallographica Section B Structural Science ◽

10.1107/s0108768195011773 ◽

1996 ◽

Vol 52 (3) ◽

pp. 487-499 ◽

Cited By ~ 11

Author(s):

M. Kubicki ◽

T. W. Kindopp ◽

M. V. Capparelli ◽

P. W. Codding

Keyword(s):

Hydrogen Bond ◽

Hydrogen Bonding ◽

Binding Site ◽

Three Dimensional ◽

Hydrogen Bonding Pattern ◽

Wide Range ◽

Show Evidence ◽

Additional Hydrogen Bond ◽

Hydrogen Bond Patterns ◽

Solvent Molecules

The crystal structures of five 1,4-dihydro-2,3-quinoxalinediones, antagonists of the NMDA modulatory glycine binding site on the excitary amino acid (EAA) receptor complex, have been determined: (I) 6,7-dinitro-1,4-dihydro-2,3-quinoxalinedione (DNQX); (II) 5,7-dinitro-1,4-dihydro-2,3-quinoxalinedione (MNQX); (III) 6-nitro-1,4-dihydro-2,3-quinoxalinedione hydrate; (IV) 6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione; (V) 5,7-dichloro-1,4-dihydro-2,3-quinoxalinedione dimethylformamide. The crystal structure of the most active compound (II) contains a unique intramolecular N—H...O(NO2) hydrogen bond, which may be important for activity, as semiempirical calculations show that this bond is stable over a wide range of dihedral angles between the planes of the molecule and of the nitro group. In the other compounds the intermolecular hydrogen bonds connect molecules into three-dimensional networks. In compounds (I), (III) and (IV) head-to-tail: π-stacking is found between molecules connected by a center of symmetry. The geometries of the hydrogen-bonded —NH—C=O fragments show evidence of π-cooperativity or resonance-assisted hydrogen bonding. Graph-set analysis of the hydrogen-bond patterns of quinoxalinedione derivatives shows a tendency to form two types of hydrogen-bonding motifs: a centrosymmetric dimeric ring and an infinite chain. Even though this pattern may be modified by the presence of additional hydrogen-bond acceptors and/or donors, as well as by solvent molecules, general similarities have been found. Comparison of all quinoxalinedione structures suggests that the hydrogen-bonding pattern necessary for the biological activity at the glycine binding site contains one donor and two acceptors.

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