Computational Studies of Catalytic Loop Dynamics in Yersinia Protein Tyrosine Phosphatase Using Pathway Optimization Methods

Hua Deng, Shan Ke, Robert Callender, Gurusamy Balakrishnan, Thomas G. Spiro, Eric R. May, Charles L. Brooks

Research output: Contribution to journalArticle

Abstract

Yersinia Protein Tyrosine Phosphatase (YopH) is the most efficient enzyme among all known PTPases and relies on its catalytic loop movements for substrate binding and catalysis. Fluorescence, NMR, and UV resonance Raman (UVRR) techniques have been used to study the thermodynamic and dynamic properties of the loop motions. In this study, a computational approach based on the pathway refinement methods nudged elastic band (NEB) and harmonic Fourier beads (HFB) has been developed to provide structural interpretations for the experimentally observed kinetic processes. In this approach, the minimum potential energy pathways for the loop open/closure conformational changes were determined by NEB using a one-dimensional global coordinate. Two dimensional data analyses of the NEB results were performed as an efficient method to qualitatively evaluate the energetics of transitions along several specific physical coordinates. The free energy barriers for these transitions were then determined more precisely using the HFB method. Kinetic parameters were estimated from the energy barriers using transition state theory and compared against experimentally determined kinetic parameters. When the calculated energy barriers are calibrated by a simple "scaling factor", as have been done in our previous vibrational frequency calculations to explain the ligand frequency shift upon its binding to protein, it is possible to make structural interpretations of several observed enzyme dynamic rates. For example, the nanosecond kinetics observed by fluorescence anisotropy may be assigned to the translational motion of the catalytic loop and microsecond kinetics observed in fluorescence T-jump can be assigned to the loop backbone dihedral angle flipping. Furthermore, we can predict that a Trp354 conformational conversion associated with the loop movements would occur on the tens of nanoseconds time scale, to be verified by future UVRR T-jump studies.

Original languageEnglish (US)
JournalJournal of Physical Chemistry B
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Protein Tyrosine Phosphatases
phosphatases
tyrosine
Energy barriers
Phosphatases
Fluorescence
proteins
Proteins
Kinetic parameters
optimization
Kinetics
Enzymes
kinetics
Enzyme kinetics
Vibrational spectra
Dihedral angle
Potential energy
beads
fluorescence
Catalysis

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

Cite this

Computational Studies of Catalytic Loop Dynamics in Yersinia Protein Tyrosine Phosphatase Using Pathway Optimization Methods. / Deng, Hua; Ke, Shan; Callender, Robert; Balakrishnan, Gurusamy; Spiro, Thomas G.; May, Eric R.; Brooks, Charles L.

In: Journal of Physical Chemistry B, 01.01.2019.

Research output: Contribution to journalArticle

@article{a21d6d3126744a0a9bc69547c6c39c26,
title = "Computational Studies of Catalytic Loop Dynamics in Yersinia Protein Tyrosine Phosphatase Using Pathway Optimization Methods",
abstract = "Yersinia Protein Tyrosine Phosphatase (YopH) is the most efficient enzyme among all known PTPases and relies on its catalytic loop movements for substrate binding and catalysis. Fluorescence, NMR, and UV resonance Raman (UVRR) techniques have been used to study the thermodynamic and dynamic properties of the loop motions. In this study, a computational approach based on the pathway refinement methods nudged elastic band (NEB) and harmonic Fourier beads (HFB) has been developed to provide structural interpretations for the experimentally observed kinetic processes. In this approach, the minimum potential energy pathways for the loop open/closure conformational changes were determined by NEB using a one-dimensional global coordinate. Two dimensional data analyses of the NEB results were performed as an efficient method to qualitatively evaluate the energetics of transitions along several specific physical coordinates. The free energy barriers for these transitions were then determined more precisely using the HFB method. Kinetic parameters were estimated from the energy barriers using transition state theory and compared against experimentally determined kinetic parameters. When the calculated energy barriers are calibrated by a simple {"}scaling factor{"}, as have been done in our previous vibrational frequency calculations to explain the ligand frequency shift upon its binding to protein, it is possible to make structural interpretations of several observed enzyme dynamic rates. For example, the nanosecond kinetics observed by fluorescence anisotropy may be assigned to the translational motion of the catalytic loop and microsecond kinetics observed in fluorescence T-jump can be assigned to the loop backbone dihedral angle flipping. Furthermore, we can predict that a Trp354 conformational conversion associated with the loop movements would occur on the tens of nanoseconds time scale, to be verified by future UVRR T-jump studies.",
author = "Hua Deng and Shan Ke and Robert Callender and Gurusamy Balakrishnan and Spiro, {Thomas G.} and May, {Eric R.} and Brooks, {Charles L.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1021/acs.jpcb.9b06759",
language = "English (US)",
journal = "Journal of Physical Chemistry B Materials",
issn = "1520-6106",
publisher = "American Chemical Society",

}

TY - JOUR

T1 - Computational Studies of Catalytic Loop Dynamics in Yersinia Protein Tyrosine Phosphatase Using Pathway Optimization Methods

AU - Deng, Hua

AU - Ke, Shan

AU - Callender, Robert

AU - Balakrishnan, Gurusamy

AU - Spiro, Thomas G.

AU - May, Eric R.

AU - Brooks, Charles L.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Yersinia Protein Tyrosine Phosphatase (YopH) is the most efficient enzyme among all known PTPases and relies on its catalytic loop movements for substrate binding and catalysis. Fluorescence, NMR, and UV resonance Raman (UVRR) techniques have been used to study the thermodynamic and dynamic properties of the loop motions. In this study, a computational approach based on the pathway refinement methods nudged elastic band (NEB) and harmonic Fourier beads (HFB) has been developed to provide structural interpretations for the experimentally observed kinetic processes. In this approach, the minimum potential energy pathways for the loop open/closure conformational changes were determined by NEB using a one-dimensional global coordinate. Two dimensional data analyses of the NEB results were performed as an efficient method to qualitatively evaluate the energetics of transitions along several specific physical coordinates. The free energy barriers for these transitions were then determined more precisely using the HFB method. Kinetic parameters were estimated from the energy barriers using transition state theory and compared against experimentally determined kinetic parameters. When the calculated energy barriers are calibrated by a simple "scaling factor", as have been done in our previous vibrational frequency calculations to explain the ligand frequency shift upon its binding to protein, it is possible to make structural interpretations of several observed enzyme dynamic rates. For example, the nanosecond kinetics observed by fluorescence anisotropy may be assigned to the translational motion of the catalytic loop and microsecond kinetics observed in fluorescence T-jump can be assigned to the loop backbone dihedral angle flipping. Furthermore, we can predict that a Trp354 conformational conversion associated with the loop movements would occur on the tens of nanoseconds time scale, to be verified by future UVRR T-jump studies.

AB - Yersinia Protein Tyrosine Phosphatase (YopH) is the most efficient enzyme among all known PTPases and relies on its catalytic loop movements for substrate binding and catalysis. Fluorescence, NMR, and UV resonance Raman (UVRR) techniques have been used to study the thermodynamic and dynamic properties of the loop motions. In this study, a computational approach based on the pathway refinement methods nudged elastic band (NEB) and harmonic Fourier beads (HFB) has been developed to provide structural interpretations for the experimentally observed kinetic processes. In this approach, the minimum potential energy pathways for the loop open/closure conformational changes were determined by NEB using a one-dimensional global coordinate. Two dimensional data analyses of the NEB results were performed as an efficient method to qualitatively evaluate the energetics of transitions along several specific physical coordinates. The free energy barriers for these transitions were then determined more precisely using the HFB method. Kinetic parameters were estimated from the energy barriers using transition state theory and compared against experimentally determined kinetic parameters. When the calculated energy barriers are calibrated by a simple "scaling factor", as have been done in our previous vibrational frequency calculations to explain the ligand frequency shift upon its binding to protein, it is possible to make structural interpretations of several observed enzyme dynamic rates. For example, the nanosecond kinetics observed by fluorescence anisotropy may be assigned to the translational motion of the catalytic loop and microsecond kinetics observed in fluorescence T-jump can be assigned to the loop backbone dihedral angle flipping. Furthermore, we can predict that a Trp354 conformational conversion associated with the loop movements would occur on the tens of nanoseconds time scale, to be verified by future UVRR T-jump studies.

UR - http://www.scopus.com/inward/record.url?scp=85072509504&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072509504&partnerID=8YFLogxK

U2 - 10.1021/acs.jpcb.9b06759

DO - 10.1021/acs.jpcb.9b06759

M3 - Article

C2 - 31437399

AN - SCOPUS:85072509504

JO - Journal of Physical Chemistry B Materials

JF - Journal of Physical Chemistry B Materials

SN - 1520-6106

ER -