Solvent Entropy Contributions to Catalytic Activity in Designed and Optimized Kemp Eliminases

Belsare, Saurabh; Pattni, Viren; Heyden, Matthias; Head-Gordon, Teresa

doi:10.1021/acs.jpcb.7b07526

Title: Solvent Entropy Contributions to Catalytic Activity in Designed and Optimized Kemp Eliminases

Abstract

This work reports on the role of solvation for enzymatic catalysis in two distinct, artificially designed Kemp Eliminases, KE07 and KE70, and mutated variants that were optimized by laboratory directed evolution. Using a spatially resolved analysis of hydration patterns, intermolecular vibrations, and local solvent entropies, we identify distinct classes of hydration water and follow their changes upon substrate binding and transition state formation for the designed KE07 and KE70 enzymes and their evolved variants. We observe that differences in hydration of the enzymatic systems are concentrated in the active site and undergo significant changes during substrate recruitment. For KE07, directed evolution reduces variations in the hydration of the polar catalytic center upon substrate binding, preserving strong protein-water interactions, while the evolved enzyme variant of KE70 features a more hydrophobic reaction center for which the expulsion of low-entropy water molecules upon substrate binding is substantially enhanced. While our analysis suggests a system-dependent role of solvation for the substrate binding process, we identify more subtle changes in solvation for the transition state formation, which are less affected by directed evolution.

Authors:

Belsare, Saurabh ^[1]; Pattni, Viren ^[2];

^[2];

^[3]

Univ. of California, Berkeley, CA (United States)
Max-Planck-Institut fur Kohlenforschung (Germany)
Univ. of California, Berkeley, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

Publication Date:: Tue Sep 12 00:00:00 EDT 2017

Research Org.:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Org.:: USDOE Office of Science (SC), Basic Energy Sciences (BES); German Research Foundation (DFG)

OSTI Identifier:: 1532319

Grant/Contract Number:: AC02-05CH11231

Resource Type:: Accepted Manuscript

Journal Name:: Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry

Additional Journal Information:: Journal Volume: 122; Journal Issue: 21; Journal ID: ISSN 1520-6106

Publisher:: American Chemical Society

Country of Publication:: United States

Language:: English

Subject:: 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats


                    Belsare, Saurabh, Pattni, Viren, Heyden, Matthias, and Head-Gordon, Teresa. Solvent Entropy Contributions to Catalytic Activity in Designed and Optimized Kemp Eliminases.  United States: N. p., 2017. 
Web.  doi:10.1021/acs.jpcb.7b07526.

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                    Belsare, Saurabh, Pattni, Viren, Heyden, Matthias, & Head-Gordon, Teresa. Solvent Entropy Contributions to Catalytic Activity in Designed and Optimized Kemp Eliminases.  United States.  https://doi.org/10.1021/acs.jpcb.7b07526

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                    Belsare, Saurabh, Pattni, Viren, Heyden, Matthias, and Head-Gordon, Teresa. Tue .  
"Solvent Entropy Contributions to Catalytic Activity in Designed and Optimized Kemp Eliminases".  United States.  https://doi.org/10.1021/acs.jpcb.7b07526.  https://www.osti.gov/servlets/purl/1532319.

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@article{osti_1532319,

  title        = {Solvent Entropy Contributions to Catalytic Activity in Designed and Optimized Kemp Eliminases},

  author       = {Belsare, Saurabh and Pattni, Viren and Heyden, Matthias and Head-Gordon, Teresa},

  abstractNote = {This work reports on the role of solvation for enzymatic catalysis in two distinct, artificially designed Kemp Eliminases, KE07 and KE70, and mutated variants that were optimized by laboratory directed evolution. Using a spatially resolved analysis of hydration patterns, intermolecular vibrations, and local solvent entropies, we identify distinct classes of hydration water and follow their changes upon substrate binding and transition state formation for the designed KE07 and KE70 enzymes and their evolved variants. We observe that differences in hydration of the enzymatic systems are concentrated in the active site and undergo significant changes during substrate recruitment. For KE07, directed evolution reduces variations in the hydration of the polar catalytic center upon substrate binding, preserving strong protein-water interactions, while the evolved enzyme variant of KE70 features a more hydrophobic reaction center for which the expulsion of low-entropy water molecules upon substrate binding is substantially enhanced. While our analysis suggests a system-dependent role of solvation for the substrate binding process, we identify more subtle changes in solvation for the transition state formation, which are less affected by directed evolution.},

  doi          = {10.1021/acs.jpcb.7b07526},

  journal      = {Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry},

  number       = 21,

  volume       = 122,

  place        = {United States},

  year         = {Tue Sep 12 00:00:00 EDT 2017},

  month        = {Tue Sep 12 00:00:00 EDT 2017}

}

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Journal Article:

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https://doi.org/10.1021/acs.jpcb.7b07526

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Cited by: 11 works

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Figures / Tables:

Figure 1: (A) Kemp Eliminase KE07 enzyme and (B) the targeted catalytic reaction. The catalytic (red) and additional stabilizing residues (cyan) create the designed KE07 enzyme. The mutations introduced by laboratory directed evolution (orange) result in an improved variant R7.2 with an increased catalytic turnover rate. The substrate is shownmore »

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Similar Records

Title: Solvent Entropy Contributions to Catalytic Activity in Designed and Optimized Kemp Eliminases

Abstract

Citation Formats

Figures / Tables:

Mechanism of Chorismate Mutase: Contribution of Conformational Restriction to Catalysis in the Claisen Rearrangement journal, December 1999

Electrostatic Basis for Enzyme Catalysis journal, August 2006

The Importance of the Scaffold for de Novo Enzymes: A Case Study with Kemp Eliminase journal, April 2017

Bulk-solvent and hydration-shell fluctuations, similar to - and -fluctuations in glasses, control protein motions and functions journal, September 2004

Protein folding is slaved to solvent motions journal, October 2006

Hydration Water Dynamics Near Biological Interfaces journal, December 2008

Hydration Dynamics Near a Model Protein Surface journal, March 2004

Role of Water in Stabilizing Ferricyanide Trianion and Ion-Induced Effects to the Hydrogen-Bonding Water Network at Long Distance journal, January 2015

An extended dynamical hydration shell around proteins journal, December 2007

The role of side chain entropy and mutual information for improving the de novo design of Kemp eliminases KE07 and KE70 journal, January 2016

Evaluation and ranking of enzyme designs: Evaluation and Ranking of Enzyme Designs journal, July 2010

The two-phase model for calculating thermodynamic properties of liquids from molecular dynamics: Validation for the phase diagram of Lennard-Jones fluids journal, December 2003

Two-Phase Thermodynamic Model for Efficient and Accurate Absolute Entropy of Water from Molecular Dynamics Simulations journal, June 2010

Distinct Protein Hydration Water Species Defined by Spatially Resolved Spectra of Intermolecular Vibrations journal, July 2017

Thermodynamic Properties of a Rigid‐Sphere Fluid journal, July 1970

On the absolute thermodynamics of water from computer simulations: A comparison of first-principles molecular dynamics, reactive and empirical force fields journal, December 2012

Kemp elimination catalysts by computational enzyme design journal, March 2008

Comparative Protein Structure Modeling Using MODELLER journal, September 2014

Comparative Protein Structure Modeling Using MODELLER journal, June 2016

OpenMM 4: A Reusable, Extensible, Hardware Independent Library for High Performance Molecular Simulation journal, November 2012

Polarizable Atomic Multipole Water Model for Molecular Mechanics Simulation journal, May 2003

Polarizable Atomic Multipole-Based Molecular Mechanics for Organic Molecules journal, August 2011

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Characterization of the Local Structure in Liquid Water by Various Order Parameters journal, June 2015

Protein hydration dynamics in aqueous solution journal, January 1996

Description of Hydration Water in Protein (Green Fluorescent Protein) Solution journal, November 2016

Biological water at the protein surface: Dynamical solvation probed directly with femtosecond resolution journal, February 2002

Dynamics in Protein Powders on the Nanosecond–Picosecond Time Scale Are Dominated by Localized Motions journal, September 2013

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Disassembling solvation free energies into local contributions—Toward a microscopic understanding of solvation processes journal, July 2018

Mechanism of Chorismate Mutase: Contribution of Conformational Restriction to Catalysis in the Claisen Rearrangement
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Electrostatic Basis for Enzyme Catalysis
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The Importance of the Scaffold for de Novo Enzymes: A Case Study with Kemp Eliminase
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Bulk-solvent and hydration-shell fluctuations, similar to - and -fluctuations in glasses, control protein motions and functions
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Protein folding is slaved to solvent motions
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Hydration Water Dynamics Near Biological Interfaces
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Hydration Dynamics Near a Model Protein Surface
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Role of Water in Stabilizing Ferricyanide Trianion and Ion-Induced Effects to the Hydrogen-Bonding Water Network at Long Distance
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An extended dynamical hydration shell around proteins
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The role of side chain entropy and mutual information for improving the de novo design of Kemp eliminases KE07 and KE70
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Evaluation and ranking of enzyme designs: Evaluation and Ranking of Enzyme Designs
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The two-phase model for calculating thermodynamic properties of liquids from molecular dynamics: Validation for the phase diagram of Lennard-Jones fluids
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Two-Phase Thermodynamic Model for Efficient and Accurate Absolute Entropy of Water from Molecular Dynamics Simulations
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Distinct Protein Hydration Water Species Defined by Spatially Resolved Spectra of Intermolecular Vibrations
journal, July 2017

Thermodynamic Properties of a Rigid‐Sphere Fluid
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On the absolute thermodynamics of water from computer simulations: A comparison of first-principles molecular dynamics, reactive and empirical force fields
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Kemp elimination catalysts by computational enzyme design
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Comparative Protein Structure Modeling Using MODELLER
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Comparative Protein Structure Modeling Using MODELLER
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OpenMM 4: A Reusable, Extensible, Hardware Independent Library for High Performance Molecular Simulation
journal, November 2012

Polarizable Atomic Multipole Water Model for Molecular Mechanics Simulation
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Polarizable Atomic Multipole-Based Molecular Mechanics for Organic Molecules
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Is the first hydration shell of lysozyme of higher density than bulk water?
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Characterization of the Local Structure in Liquid Water by Various Order Parameters
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Protein hydration dynamics in aqueous solution
journal, January 1996

Description of Hydration Water in Protein (Green Fluorescent Protein) Solution
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