Skip to main content
OSTI.GOVU.S. Department of Energy Office of Scientific and Technical Information
U.S. Department of Energy
Office of Scientific and Technical Information
 

Structural Coupling Throughout the Active Site Hydrogen Bond Networks of Ketosteroid Isomerase and Photoactive Yellow Protein

Journal Article · · Journal of the American Chemical Society
DOI:https://doi.org/10.1021/jacs.8b01596· OSTI ID:1476146
 [1];  [1];  [1];  [2];  [3];  [2];  [4];  [5];  [2];  [1]
  1. Stanford Univ., Stanford, CA (United States)
  2. Stanford Univ., Stanford, CA (United States); SLAC National Accelerator Lab., Menlo Park, CA (United States)
  3. Stanford Univ., Stanford, CA (United States); SLAC National Accelerator Lab., Menlo Park, CA (United States); Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)
  4. SLAC National Accelerator Lab., Menlo Park, CA (United States)
  5. Stanford Univ., Stanford, CA (United States); California State Univ. Long Beach, Long Beach, CA (United States)
+ Show Author Affiliations
Hydrogen bonds are fundamental to biological systems and are regularly found in networks implicated in folding, molecular recognition, catalysis, and allostery. Given their ubiquity, we asked the fundamental questions of whether, and to what extent, hydrogen bonds within networks are structurally coupled. To address these questions, we turned to three protein systems, two variants of ketosteroid isomerase and one of photoactive yellow protein. We perturbed their hydrogen bond networks via a combination of site-directed mutagenesis and unnatural amino acid substitution, and we used 1H NMR and high-resolution X-ray crystallography to determine the effects of these perturbations on the lengths of the two oxyanion hole hydrogen bonds that are donated to negatively charged transition state analogs. Perturbations that lengthened or shortened one of the oxyanion hole hydrogen bonds had the opposite effect on the other. The oxyanion hole hydrogen bonds were also affected by distal hydrogen bonds in the network, with smaller perturbations for more remote hydrogen bonds. Across 19 measurements in three systems, the length change in one oxyanion hole hydrogen bond was propagated to the other, by a factor of –0.30 ± 0.03. This common effect suggests that hydrogen bond coupling is minimally influenced by the remaining protein scaffold. The observed coupling is reproduced by molecular mechanics and quantum mechanics/molecular mechanics (QM/MM) calculations for changes to a proximal oxyanion hole hydrogen bond. However, effects from distal hydrogen bonds are reproduced only by QM/MM, suggesting the importance of polarization in hydrogen bond coupling. These results deepen our understanding of hydrogen bonds and their networks, providing strong evidence for long-range coupling and for the extent of this coupling. In conclusion, we provide a broadly predictive quantitative relationship that can be applied to and can be further tested in new systems.
Research Organization:
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
Sponsoring Organization:
USDOE
Grant/Contract Number:
AC02-76SF00515
OSTI ID:
1476146
Journal Information:
Journal of the American Chemical Society, Journal Name: Journal of the American Chemical Society Journal Issue: 31 Vol. 140; ISSN 0002-7863
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
English

References (105)

High-Precision Measurement of Hydrogen Bond Lengths in Proteins by Nuclear Magnetic Resonance Methods journal May 1999
The Hydrogen Bond in the Solid State journal January 2002
Computational Enzyme Design journal March 2013
A comparison of successful and failed protein interface designs highlights the challenges of designing buried hydrogen bonds journal November 2012
Substituent effects on the physical properties and pKa of phenol journal January 2001
Hydrogen Bonding in Biological Structures book January 1991
De novo protein design: what are we learning? journal December 1991
De novo protein design: from molten globules to native-like states journal August 1993
The hydrogen bond in molecular recognition journal January 1987
On the Role of Electrostatic Interactions in the Design of Protein–Protein Interfaces journal April 2002
NMR studies of strong hydrogen bonds in enzymes and in a model compound journal September 2000
Understanding enzymic catalysis: the importance of short, strong hydrogen bonds journal April 1997
A hydrogen bond network in the active site of Anabaena ferredoxin-NADP+ reductase modulates its catalytic efficiency journal February 2014
Transient Non-native Hydrogen Bonds Promote Activation of a Signaling Protein journal December 2009
Computational Design of a New Hydrogen Bond Network and at Least a 300-fold Specificity Switch at a Protein−Protein Interface journal August 2006
Structural bases of hydrogen tunneling in enzymes: progress and puzzles journal December 2004
Membrane protein folding: how important are hydrogen bonds? journal February 2011
Mapping the Hydrogen Bond Networks in the Catalytic Subunit of Protein Kinase A Using H/D Fractionation Factors journal June 2015
Hydrogen Bonds: Simple after All? journal April 2018
Hydrogen–Deuterium Exchange of Lipoxygenase Uncovers a Relationship between Distal, Solvent Exposed Protein Motions and the Thermal Activation Barrier for Catalytic Proton-Coupled Electron Tunneling journal June 2017
Dynamically Achieved Active Site Precision in Enzyme Catalysis journal December 2014
Predicting Hydrogen-Bond Strengths from Acid−Base Molecular Properties. The p K a Slide Rule: Toward the Solution of a Long-Lasting Problem journal January 2009
1.4 .ANG. Structure of Photoactive Yellow Protein, a Cytosolic Photoreceptor: Unusual Fold, Active Site, and Chromophore journal May 1995
.alpha.-Fluoro Acid and .alpha.-Fluoro Amide Analogs of Acetyl-CoA as Inhibitors of Citrate Synthase: Effect of pKa Matching on Binding Affinity and Hydrogen Bond Length journal November 1995
Mechanistic Implications of Methylglyoxal Synthase Complexed with Phosphoglycolohydroxamic Acid As Observed by X-ray Crystallography and NMR Spectroscopy † journal June 2001
The Catalytic Power of Ketosteroid Isomerase Investigated by Computer Simulation † journal December 2002
Proton Affinity of the Oxyanion Hole in the Active Site of Ketosteroid Isomerase journal February 2010
Importance of Protein Dynamics during Enzymatic C–H Bond Cleavage Catalysis journal February 2013
Fundamental Challenges in Mechanistic Enzymology: Progress toward Understanding the Rate Enhancements of Enzymes journal March 2013
Hydrogen Bonding Networks Tune Proton-Coupled Redox Steps during the Enzymatic Six-Electron Conversion of Nitrite to Ammonia journal August 2014
Hydrogen Bond Coupling in the Ketosteroid Isomerase Active Site journal July 2009
NMR Studies of the Role of Hydrogen Bonding in the Mechanism of Triosephosphate Isomerase † journal December 1997
Substituent Effects on the Binding of Phenols to the D38N Mutant of 3-Oxo-Δ 5 -steroid Isomerase. A Probe for the Nature of Hydrogen Bonding to the Intermediate † journal January 1998
Electrophilic Assistance by Asp-99 of 3-Oxo-Δ 5 -steroid Isomerase journal June 1998
Contribution of the Hydrogen-Bond Network Involving a Tyrosine Triad in the Active Site to the Structure and Function of a Highly Proficient Ketosteroid Isomerase from Pseudomonas putida Biotype B † , ‡ journal April 2000
Molecular Architecture and Biological Reactions: Answers to many basic problems of biology—nature of growth, mechanism of duplication of viruses and genes, action of enzymes, mechanism, of physiological activity of drugs, hormones, and vitamins, structure and action of nerve and brain tissue—may lie in knowledge of molecular structure and intermolecular reactions journal May 1946
The Ionic Hydrogen Bond journal January 2005
Microscopic rate constants for the acetate ion catalyzed isomerization of 5-androstene-3,17-dione to 4-androstene-3,17-dione: a model for steroid isomerase journal May 1991
Proton, deuterium, and tritium nuclear magnetic resonance of intramolecular hydrogen bonds. Isotope effects and the shape of the potential energy function journal December 1978
Structures and isotopic fractionation factors of complexes, A1HA2- journal May 1980
The Nature of the Chemical Bond. Application of Results Obtained from the Quantum Mechanics and from a Theory of Paramagnetic Susceptibility to the Structure of Molecules journal April 1931
Characterization of Fluxional Hydrogen-Bonded Complexes of Acetic Acid and Acetate by NMR:  Geometries and Isotope and Solvent Effects journal May 2004
Reaction Pathways of Proton Transfer in Hydrogen-Bonded Phenol–Carboxylate Complexes Explored by Combined UV–Vis and NMR Spectroscopy journal May 2011
Supramolecular Polymers in Aqueous Medium: Rational Design Based on Directional Hydrophobic Interactions journal October 2011
The Role of Large-Scale Motions in Catalysis by Dihydrofolate Reductase journal December 2011
Using Unnatural Amino Acids to Probe the Energetics of Oxyanion Hole Hydrogen Bonds in the Ketosteroid Isomerase Active Site journal May 2014
Determination of Hydrogen Bond Structure in Water versus Aprotic Environments To Test the Relationship Between Length and Stability journal April 2015
Identification of Hydroxyl Protons, Determination of Their Exchange Dynamics, and Characterization of Hydrogen Bonding in a Microcrystallin Protein journal February 2010
Evaluation of the Catalytic Contribution from a Positioned General Base in Ketosteroid Isomerase journal July 2016
Short, Strong Hydrogen Bonds in the Gas Phase and in Solution:  Theoretical Exploration of p K a Matching and Environmental Effects on the Strengths of Hydrogen Bonds and Their Potential Roles in Enzymatic Catalysis journal July 1998
Toward a General Theory of Hydrogen Bonding:  The Short, Strong Hydrogen Bond [HOH···OH] - journal October 2000
Ab Initio Quantum Chemistry for Protein Structures journal October 2012
The Charge Transfer Problem in Density Functional Theory Calculations of Aqueously Solvated Molecules journal October 2013
Picosecond-Resolved Fluorescent Probes at Functionally Distinct Tryptophans within a Thermophilic Alcohol Dehydrogenase: Relationship of Temperature-Dependent Changes in Fluorescence to Catalysis journal June 2014
Solvent-Induced Red-Shifts for the Proton Stretch Vibrational Frequency in a Hydrogen-Bonded Complex. 1. A Valence Bond-Based Theoretical Approach journal May 2014
On p K a Matching as a Requirement To Form a Low-Barrier Hydrogen Bond. A Theoretical Study in Gas Phase journal May 1997
Enzyme dynamics and hydrogen tunnelling in a thermophilic alcohol dehydrogenase journal June 1999
Pathways of allosteric regulation in Hsp70 chaperones journal September 2015
A perspective on biological catalysis journal October 1996
Localized thermodynamic coupling between hydrogen bonding and microenvironment polarity substantially stabilizes proteins journal June 2009
Computational redesign of protein-protein interaction specificity journal March 2004
Trimethylglycine complexes with carboxylic acids and HF: solvation by a polar aprotic solvent journal January 2011
A cartography of the van der Waals territories journal January 2013
Sequence optimization and designability of enzyme active sites journal August 2005
Changes in hydrogen-bond strengths explain reduction potentials in 10 rubredoxin variants journal September 2005
Low-barrier hydrogen bond in photoactive yellow protein journal January 2009
Hydrogen bond dynamics in the active site of photoactive yellow protein journal May 2009
Dissecting the paradoxical effects of hydrogen bond mutations in the ketosteroid isomerase oxyanion hole journal January 2010
Impaired protein conformational landscapes as revealed in anomalous Arrhenius prefactors journal June 2011
Catalysis by dihydrofolate reductase and other enzymes arises from electrostatic preorganization, not conformational motions journal August 2011
Quantitative dissection of hydrogen bond-mediated proton transfer in the ketosteroid isomerase active site journal June 2013
Unraveling the role of protein dynamics in dihydrofolate reductase catalysis journal September 2013
Energy considerations show that low-barrier hydrogen bonds do not offer a catalytic advantage over ordinary hydrogen bonds journal November 1996
Identification of a Long-range Protein Network That Modulates Active Site Dynamics in Extremophilic Alcohol Dehydrogenases journal March 2013
Molecular Basis of the General Base Catalysis of an α/β-Hydrolase Catalytic Triad journal May 2014
Hydrogen-Bonding: An Update journal February 1995
Difficulties in applying pure Kohn–Sham density functional theory electronic structure methods to protein molecules journal January 2012
Hydrogen bonds and salt bridges across protein-protein interfaces journal September 1997
Importance of Hydrogen-Bond Formation in Stabilizing the Transition State of Subtilisin
  • Wells, J. A.; Cunningham, B. C.; Graycar, T. P.
  • Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences, Vol. 317, Issue 1540, p. 415-423 https://doi.org/10.1098/rsta.1986.0051
journal April 1986
A systematic study of coordinate precision in X-ray structure analyses. I. Descriptive statistics and predictive estimates of e.s.d.'s for C atoms journal March 1995
A systematic study of coordinate precision in X-ray structure analyses. II. Predictive estimates of e.s.d.'s for the general-atom case journal March 1995
The Cambridge Structural Database: a quarter of a million crystal structures and rising journal May 2002
The correlation between hydrogen-bond lengths and proton chemical shifts in crystals journal August 1986
Lengthening of the covalent O–H bond in O–H ... O hydrogen bonds re-examined from low-temperature neutron diffraction data of organic compounds journal June 1994
Structure of photoactive yellow protein (PYP) E46Q mutant at 1.2 Å resolution suggests how Glu46 controls the spectroscopic and kinetic characteristics of PYP journal November 2004
Allostery and cooperativity revisited journal August 2008
Do all backbone polar groups in proteins form hydrogen bonds? journal July 2005
A Perspective on Enzyme Catalysis journal August 2003
The Dynamic Energy Landscape of Dihydrofolate Reductase Catalysis journal September 2006
Insights into Current Limitations of Density Functional Theory journal August 2008
Symmetries of Hydrogen Bonds in Solution journal December 1994
A low-barrier hydrogen bond in the catalytic triad of serine proteases journal June 1994
Low-barrier hydrogen bonds and enzymic catalysis journal June 1994
Hydrogen Tunneling Links Protein Dynamics to Enzyme Catalysis journal June 2013
Enzymatic Transition States, Transition-State Analogs, Dynamics, Thermodynamics, and Lifetimes journal July 2011
Hydrogen Bonding, Hydrophobicity, Packing, and Protein Folding journal June 1993
Thermodynamics of Partly Folded Intermediates in Proteins journal June 1995
Challenges in Enzyme Mechanism and Energetics journal June 2003
Relating Protein Motion to Catalysis journal June 2006
Structure and Energetics of the Hydrogen-Bonded Backbone in Protein Folding journal June 2008
“Strong” Hydrogen Bonds in Chemistry and Biology journal October 1997
Testing Electrostatic Complementarity in Enzyme Catalysis: Hydrogen Bonding in the Ketosteroid Isomerase Oxyanion Hole journal March 2006
Structure and Photoreaction of Photoactive Yellow Protein, a Structural Prototype of the PAS Domain Superfamily† journal January 2007
Isotope Effects on Chemical Shifts as an Analytical Tool in Structural Studies of Intramolecular Hydrogen Bonded Compounds journal January 2000
Molecular basis for allosteric specificity regulation in class Ia ribonucleotide reductase from Escherichia coli journal January 2016

Cited By (4)

Synergistic promotion by intramolecular hydrogen bonding: a bi-functionally catalyzed cascade reaction for the synthesis of enantiopure chromenopyrrolidines journal January 2019
Symmetry and 1 H NMR chemical shifts of short hydrogen bonds: impact of electronic and nuclear quantum effects journal January 2020
Unraveling the structural and chemical features of biological short hydrogen bonds journal January 2019
Assessment of enzyme active site positioning and tests of catalytic mechanisms through X-ray–derived conformational ensembles journal December 2020

Similar Records

Testing Electrostatic Complementarity in Enzyme Catalysis: Hydrogen Bonding in the Ketosteroid Isomerase Oxyanion Hole
Journal Article · Mon Mar 27 19:00:00 EST 2006 · PLoS Biology (Online) · OSTI ID:1627145
Testing Geometrical Discrimination Within An Enzyme Active Site: Constrained Hydrogen Bonding in the Ketosteroid Isomerase Oxyanion Hole
Journal Article · Tue May 26 00:00:00 EDT 2009 · J. Am. Chem. Soc 130:13696,2008 · OSTI ID:953565
Testing Geometrical Discrimination within an Enzyme Active Site: Constrained Hydrogen Bonding in the Ketosteroid Isomerase Oxyanion Hole
Journal Article · Sun Nov 02 23:00:00 EST 2008 · J. Am. Chem. Soc. · OSTI ID:1006923

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY