Exploring the binding pathways of the 14-3-3 zeta : protein
Structural and free-energy profiles revealed by Hamiltonian
replica exchange molecular dynamics with distancefield distance
restraints

J 2017

Exploring the binding pathways of the 14-3-3 zeta : protein Structural and free-energy profiles revealed by Hamiltonian replica exchange molecular dynamics with distancefield distance restraints

NAGY, Gabor, C. OOSTENBRINK and Jozef HRITZ

Basic information

Original name

Exploring the binding pathways of the 14-3-3 zeta : protein Structural and free-energy profiles revealed by Hamiltonian replica exchange molecular dynamics with distancefield distance restraints

Authors

NAGY, Gabor (348 Hungary, belonging to the institution), C. OOSTENBRINK (40 Austria) and Jozef HRITZ (703 Slovakia, guarantor, belonging to the institution)

Edition

Plos one, San Francisco, Public Library of Science, 2017, 1932-6203

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10608 Biochemistry and molecular biology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 2.766

RIV identification code

RIV/00216224:14740/17:00095498

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1371/journal.pone.0180633

UT WoS

000406634500026

Keywords in English

SIMULATIONS; SITES; PHOSPHOSERINE; RECOGNITION; FORCE; NMR

Abstract

V originále

The 14-3-3 zeta protein family performs regulatory functions in eukaryotic organisms by binding to a large number of phosphorylated protein partners. Whilst the binding mode of the phosphopeptides within the primary 14-3-3 zeta binding site is well established based on the crystal structures of their complexes, little is known about the binding process itself. We present a computational study of the process by which phosphopeptides bind to the 14-3-3 zeta protein. Applying a novel scheme combining Hamiltonian replica exchange molecular dynamics and distancefield restraints allowed us to map and compare the most likely phosphopeptidebinding pathways to the 14-3-3 zeta protein. The most important structural changes to the protein and peptides involved in the binding process were identified. In order to bind phosphopeptides to the primary interaction site, the 14-3-3 zeta adopted a newly found wide-opened conformation. Based on our findings we additionally propose a secondary interaction site on the inner surface of the 14-3-3 zeta dimer, and a direct interference on the binding process by the flexible C-terminal tail. A minimalistic model was designed to allow for the efficient calculation of absolute binding affinities. Binding affinities calculated from the potential of mean force along the binding pathway are in line with the available experimental estimates for two of the studied systems.

Links

GF15-34684L, research and development project

Name: Efektivní výpočty volných energií a konfiguračního vzorkování protein-‐proteinových interakcí

Investor: Czech Science Foundation, Partner Agency (Austria)

LM2015085, research and development project

Name: CERIT Scientific Cloud (Acronym: CERIT-SC)

Investor: Ministry of Education, Youth and Sports of the CR, CERIT Scientific Cloud

4SGA8679, interní kód MU

Name: Structural determination of the human 14-3-3zeta in complex with a double phosphorylated human tyrosine hydroxylase 1 (Acronym: MODULATOR)

Investor: South-Moravian Region

Citovat

NAGY, Gabor, C. OOSTENBRINK and Jozef HRITZ. Exploring the binding pathways of the 14-3-3 zeta : protein Structural and free-energy profiles revealed by Hamiltonian replica exchange molecular dynamics with distancefield distance restraints. Plos one. San Francisco: Public Library of Science, 2017, vol. 12, No 7, p. nestránkováno, 30 pp. ISSN 1932-6203. Available from: https://dx.doi.org/10.1371/journal.pone.0180633.

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   keywords = {SIMULATIONS; SITES; PHOSPHOSERINE; RECOGNITION; FORCE; NMR},
   language = {eng},
   issn = {1932-6203},
   journal = {Plos one},
   title = {Exploring the binding pathways of the 14-3-3 zeta : protein Structural and free-energy profiles revealed by Hamiltonian replica exchange molecular dynamics with distancefield distance restraints},
   url = {http://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0180633&type=printable},
   volume = {12},
   year = {2017}
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TY  - JOUR
ID  - 1408304
AU  - Nagy, Gabor - Oostenbrink, C. - Hritz, Jozef
PY  - 2017
TI  - Exploring the binding pathways of the 14-3-3 zeta : protein Structural and free-energy profiles revealed by Hamiltonian replica exchange molecular dynamics with distancefield distance restraints
JF  - Plos one
VL  - 12
IS  - 7
SP  - nestránkováno
EP  - nestránkováno
PB  - Public Library of Science
SN  - 19326203
KW  - SIMULATIONS
KW  - SITES
KW  - PHOSPHOSERINE
KW  - RECOGNITION
KW  - FORCE
KW  - NMR
UR  - http://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0180633&type=printable
L2  - http://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0180633&type=printable
N2  - The 14-3-3 zeta protein family performs regulatory functions in eukaryotic organisms by binding to a large number of phosphorylated protein partners. Whilst the binding mode of the phosphopeptides within the primary 14-3-3 zeta binding site is well established based on the crystal structures of their complexes, little is known about the binding process itself. We present a computational study of the process by which phosphopeptides bind to the 14-3-3 zeta protein. Applying a novel scheme combining Hamiltonian replica exchange molecular dynamics and distancefield restraints allowed us to map and compare the most likely phosphopeptidebinding pathways to the 14-3-3 zeta protein. The most important structural changes to the protein and peptides involved in the binding process were identified. In order to bind phosphopeptides to the primary interaction site, the 14-3-3 zeta adopted a newly found wide-opened conformation. Based on our findings we additionally propose a secondary interaction site on the inner surface of the 14-3-3 zeta dimer, and a direct interference on the binding process by the flexible C-terminal tail. A minimalistic model was designed to allow for the efficient calculation of absolute binding affinities. Binding affinities calculated from the potential of mean force along the binding pathway are in line with the available experimental estimates for two of the studied systems.
ER  -

NAGY, Gabor, C. OOSTENBRINK and Jozef HRITZ. Exploring the binding pathways of the 14-3-3 zeta : protein Structural and free-energy profiles revealed by Hamiltonian replica exchange molecular dynamics with distancefield distance restraints. \textit{Plos one}. San Francisco: Public Library of Science, 2017, vol.~12, No~7, p.~nestránkováno, 30 pp. ISSN~1932-6203. Available from: https://dx.doi.org/10.1371/journal.pone.0180633.

Detailed Information on Publication Record