Open Access
Open access

Mechanism of guanosine triphosphate hydrolysis by the visual proteins arl3-rp2: Free energy reaction profiles computed with ab initio type qm/mm potentials

Khrenova M.G., Bulavko E.S., Mulashkin F.D., Nemukhin A.V.
Тип документаJournal Article
Дата публикации2021-07-01
Название журналаMolecules
ИздательMultidisciplinary Digital Publishing Institute (MDPI)
  • Organic Chemistry
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Pharmaceutical Science
  • Molecular Medicine
  • Analytical Chemistry
  • Chemistry (miscellaneous)
Краткое описание

We report the results of calculations of the Gibbs energy profiles of the guanosine triphosphate (GTP) hydrolysis by the Arl3-RP2 protein complex using molecular dynamics (MD) simulations with ab initio type QM/MM potentials. The chemical reaction of GTP hydrolysis to guanosine diphosphate (GDP) and inorganic phosphate (Pi) is catalyzed by GTPases, the enzymes, which are responsible for signal transduction in live cells. A small GTPase Arl3, catalyzing the GTP → GDP reaction in complex with the activating protein RP2, constitute an essential part of the human vision cycle. To simulate the reaction mechanism, a model system is constructed by motifs of the crystal structure of the Arl3-RP2 complexed with a substrate analog. After selection of reaction coordinates, energy profiles for elementary steps along the reaction pathway GTP + H2O → GDP + Pi are computed using the umbrella sampling and umbrella integration procedures. QM/MM MD calculations are carried out, interfacing the molecular dynamics program NAMD and the quantum chemistry program TeraChem. Ab initio type QM(DFT)/MM potentials are computed with atom-centered basis sets 6-31G** and two hybrid functionals (PBE0-D3 and ωB97x-D3) of the density functional theory, describing a large QM subsystem. Results of these simulations of the reaction mechanism are compared to those obtained with QM/MM calculations on the potential energy surface using a similar description of the QM part. We find that both approaches, QM/MM and QM/MM MD, support the mechanism of GTP hydrolysis by GTPases, according to which the catalytic glutamine side chain (Gln71, in this system) actively participates in the reaction. Both approaches distinguish two parts of the reaction: the cleavage of the phosphorus-oxygen bond in GTP coupled with the formation of Pi, and the enzyme regeneration. Newly performed QM/MM MD simulations confirmed the profile predicted in the QM/MM minimum energy calculations, called here the pathway-I, and corrected its relief at the first elementary step from the enzyme–substrate complex. The QM/MM MD simulations also revealed another mechanism at the part of enzyme regeneration leading to pathway-II. Pathway-II is more consistent with the experimental kinetic data of the wild-type complex Arl3-RP2, whereas pathway-I explains the role of the mutation Glu138Gly in RP2 slowing down the hydrolysis rate.

Пристатейные ссылки: 48
Цитируется в публикациях: 1
Biomolecular QM/MM Simulations: What Are Some of the “Burning Issues”?
Cui Q., Pal T., Xie L.
Q1 Journal of Physical Chemistry B 2021 цитирований: 11
Dynamical properties of enzyme-substrate complexes disclose substrate specificity of the SARS-CoV-2 main protease as characterized by the electron density descriptors
Khrenova M.G., Tsirelson V.G., Nemukhin A.V.
Q1 Physical Chemistry Chemical Physics 2020 цитирований: 10
Scalable molecular dynamics on CPU and GPU architectures with NAMD
Phillips J.C., Hardy D.J., Maia J.D., Stone J.E., Ribeiro J.V., Bernardi R.C., Buch R., Fiorin G., Hénin J., Jiang W., McGreevy R., Melo M.C., Radak B.K., Skeel R.D., Singharoy A., et. al.
Q1 Journal of Chemical Physics 2020 цитирований: 275
TeraChem : A graphical processing unit ‐accelerated electronic structure package for large‐scale ab initio molecular dynamics
Seritan S., Bannwarth C., Fales B.S., Hohenstein E.G., Isborn C.M., Kokkila‐Schumacher S.I., Li X., Liu F., Luehr N., Snyder J.W., Song C., Titov A.V., Ufimtsev I.S., Wang L., Martínez T.J.
Q1 Wiley Interdisciplinary Reviews: Computational Molecular Science 2020 цитирований: 24
Reaction Mechanism and Determinants for Efficient Catalysis by DszB, a Key Enzyme for Crude Oil Bio-desulfurization
Sousa J.P., Neves R.P., Sousa S.F., Ramos M.J., Fernandes P.A.
Q1 ACS Catalysis 2020 цитирований: 11
Catalytic Mechanism of Human Aldehyde Oxidase
Ferreira P., Cerqueira N.M., Fernandes P.A., Romão M.J., Ramos M.J.
Q1 ACS Catalysis 2020 цитирований: 7
Cations in motion: QM/MM studies of the dynamic and electrostatic roles of H+ and Mg2+ ions in enzyme reactions
Berta D., Buigues P.J., Badaoui M., Rosta E.
Q1 Current Opinion in Structural Biology 2020 цитирований: 12
Diversity of mechanisms in Ras-GAP catalysis of guanosine triphosphate hydrolysis revealed by molecular modeling
Grigorenko B.L., Kots E.D., Nemukhin A.V.
Q1 Organic and Biomolecular Chemistry 2019 цитирований: 10
Quantum Mechanical/Molecular Mechanical Analysis of the Catalytic Mechanism of Phosphoserine Phosphatase
Krachtus D., Smith J., Imhof P.
Q2 Molecules 2018 цитирований: 5
Binary Function of ARL3-GTP Revealed by Gene Knockouts
Hanke-Gogokhia C., Frederick J.M., Zhang H., Baehr W.
Q2 Advances in Experimental Medicine and Biology 2018 цитирований: 6
NAMD goes quantum: an integrative suite for hybrid simulations
Melo M.C., Bernardi R.C., Rudack T., Scheurer M., Riplinger C., Phillips J.C., Maia J.D., Rocha G.B., Ribeiro J.V., Stone J.E., Neese F., Schulten K., Luthey-Schulten Z.
Q1 Nature Methods 2018 цитирований: 70
Multiscale modeling of enzymes: QM-cluster, QM/MM, and QM/MM/MD: A tutorial review
Ahmadi S., Barrios Herrera L., Chehelamirani M., Hostaš J., Jalife S., Salahub D.R.
Q2 International Journal of Quantum Chemistry 2018 цитирований: 38
Amide-imide tautomerization in the glutamine side chain in enzymatic and photochemical reactions in proteins
Grigorenko B.L., Khrenova M.G., Nemukhin A.V.
Q1 Physical Chemistry Chemical Physics 2018 цитирований: 18
1. Khrenova M.G. и др. Mechanism of Guanosine Triphosphate Hydrolysis by the Visual Proteins Arl3-RP2: Free Energy Reaction Profiles Computed with Ab Initio Type QM/MM Potentials // Molecules. 2021. Т. 26. № 13. С. 3998.


DO - 10.3390/molecules26133998

UR -

TI - Mechanism of Guanosine Triphosphate Hydrolysis by the Visual Proteins Arl3-RP2: Free Energy Reaction Profiles Computed with Ab Initio Type QM/MM Potentials

T2 - Molecules

AU - Khrenova, Maria G.

AU - Bulavko, Egor S.

AU - Mulashkin, Fedor D.

AU - Nemukhin, Alexander V.

PY - 2021

DA - 2021/06/30


SP - 3998

IS - 13

VL - 26

SN - 1420-3049

ER -

BibTex |


doi = {10.3390/molecules26133998},

url = {},

year = 2021,

month = {jun},

publisher = {{MDPI} {AG}},

volume = {26},

number = {13},

pages = {3998},

author = {Maria G. Khrenova and Egor S. Bulavko and Fedor D. Mulashkin and Alexander V. Nemukhin},

title = {Mechanism of Guanosine Triphosphate Hydrolysis by the Visual Proteins Arl3-{RP}2: Free Energy Reaction Profiles Computed with Ab Initio Type {QM}/{MM} Potentials}


Khrenova, Maria G. et al. “Mechanism of Guanosine Triphosphate Hydrolysis by the Visual Proteins Arl3-RP2: Free Energy Reaction Profiles Computed with Ab Initio Type QM/MM Potentials.” Molecules 26.13 (2021): 3998. Crossref. Web.