DOI: 10.1073/pnas.1705311114
论文题名: Hidden electrostatic basis of dynamic allostery in a PDZ domain
作者: Kumawat A. ; Chakrabarty S.
刊名: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
出版年: 2017
卷: 114, 期: 29 起始页码: E5825
结束页码: E5834
语种: 英语
英文关键词: Dynamic allostery
; Electrostatic interactions
; Molecular dynamics
; PDZ domain
; Population shift
Scopus关键词: PDZ3 domain protein
; peptides and proteins
; unclassified drug
; Cript protein, rat
; ligand
; protein
; signal transducing adaptor protein
; allosteric site
; allosterism
; amino terminal sequence
; Article
; binding site
; carboxy terminal sequence
; crystal structure
; enthalpy
; hydrogen bond
; ligand binding
; molecular dynamics
; PDZ domain
; priority journal
; protein domain
; protein protein interaction
; static electricity
; allosterism
; chemistry
; entropy
; metabolism
; molecular model
; static electricity
; Adaptor Proteins, Signal Transducing
; Allosteric Regulation
; Binding Sites
; Entropy
; Ligands
; Models, Molecular
; Molecular Dynamics Simulation
; PDZ Domains
; Proteins
; Static Electricity
英文摘要: Allosteric effect implies ligand binding at one site leading to structural and/or dynamical changes at a distant site. PDZ domains are classic examples of dynamic allostery without conformational changes, where distal side-chain dynamics is modulated on ligand binding and the origin has been attributed to entropic effects. In this work, we unearth the energetic basis of the observed dynamic allostery in a PDZ3 domain protein using molecular dynamics simulations. We demonstrate that electrostatic interaction provides a highly sensitive yardstick to probe the allosteric modulation in contrast to the traditionally used structure-based parameters. There is a significant population shift in the hydrogen-bonded network and salt bridges involving side chains on ligand binding. The ligand creates a local energetic perturbation that propagates in the form of dominolike changes in interresidue interaction pattern. There are significant changes in the nature of specific interactions (nonpolar/ polar) between interresidue contacts and accompanied side-chain reorientations that drive the major redistribution of energy. Interestingly, this internal redistribution and rewiring of side-chain interactions led to large cancellations resulting in small change in the overall enthalpy of the protein, thus making it difficult to detect experimentally. In contrast to the prevailing focus on the entropic or dynamic effects, we show that the internal redistribution and population shift in specific electrostatic interactions drive the allosteric modulation in the PDZ3 domain protein. © 2017, National Academy of Sciences. All rights reserved. Citation statistics:
资源类型: 期刊论文
标识符: http://119.78.100.158/handle/2HF3EXSE/163817
Appears in Collections: 气候变化与战略
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作者单位: Kumawat, A., Academy of Scientific and Innovative Research (AcSIR), Council of Scientific and Industrial Research—National Chemical Laboratory (CSIR-NCL), Pune, 411008, India, Physical and Materials Chemistry Division, CSIR-NCL, Pune, 411008, India; Chakrabarty, S., Academy of Scientific and Innovative Research (AcSIR), Council of Scientific and Industrial Research—National Chemical Laboratory (CSIR-NCL), Pune, 411008, India, Physical and Materials Chemistry Division, CSIR-NCL, Pune, 411008, India, School of Chemical Sciences, National Institute of Science Education and Research (NISER), Bhubaneswar, 752050, India
Recommended Citation:
Kumawat A.,Chakrabarty S.. Hidden electrostatic basis of dynamic allostery in a PDZ domain[J]. Proceedings of the National Academy of Sciences of the United States of America,2017-01-01,114(29)