Exploring transition pathway and free-energy profile of large-scale protein conformational change by combining normal mode analysis and umbrella sampling molecular dynamics

The Journal of Physical Chemistry. B
Jinan WangWeiliang Zhu

Abstract

Large-scale conformational changes of proteins are usually associated with the binding of ligands. Because the conformational changes are often related to the biological functions of proteins, understanding the molecular mechanisms of these motions and the effects of ligand binding becomes very necessary. In the present study, we use the combination of normal-mode analysis and umbrella sampling molecular dynamics simulation to delineate the atomically detailed conformational transition pathways and the associated free-energy landscapes for three well-known protein systems, viz., adenylate kinase (AdK), calmodulin (CaM), and p38α kinase in the absence and presence of respective ligands. For each protein under study, the transient conformations along the conformational transition pathway and thermodynamic observables are in agreement with experimentally and computationally determined ones. The calculated free-energy profiles reveal that AdK and CaM are intrinsically flexible in structures without obvious energy barrier, and their ligand binding shifts the equilibrium from the ligand-free to ligand-bound conformation (population shift mechanism). In contrast, the ligand binding to p38α leads to a large change in free-energy barrie...Continue Reading

References

Dec 20, 1992·Journal of Molecular Biology·R ChattopadhyayaF A Quiocho
Jun 1, 1994·Protein Science : a Publication of the Protein Society·S HaywardN Go
Sep 1, 1995·Nature Structural Biology·H KuboniwaA Bax
Jun 1, 1994·Journal of Molecular Graphics·J SchlitterP Krüger
Mar 18, 1997·Proceedings of the National Academy of Sciences of the United States of America·Z WangE J Goldsmith
Sep 1, 1999·Proceedings of the National Academy of Sciences of the United States of America·C J TsaiR Nussinov
Jul 8, 2000·Trends in Cell Biology·D Chin, A R Means
Sep 7, 2000·Protein Science : a Publication of the Protein Society·L MasinoP M Bayley
Mar 16, 2002·Nature Structural Biology·Christopher PargellisJohn Regan
Apr 18, 2002·Current Opinion in Structural Biology·Tomas HanssonWilfredF van Gunsteren
Jun 28, 2002·Journal of Medicinal Chemistry·John ReganCarol Torcellini
Aug 29, 2002·Nature Structural Biology·Martin Karplus, J Andrew McCammon
Dec 19, 2002·Biophysical Chemistry·Carl-Roland RablPeter M Bayley
Sep 3, 2003·Nature Reviews. Drug Discovery·Sanjay KumarJohn C Lee
Apr 22, 2004·The Journal of Biological Chemistry·Euiyoung Bae, George N Phillips
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Jun 18, 2004·Journal of Molecular Biology·Qiang CuiMartin Karplus
Jul 23, 2004·The Journal of Chemical Physics·Donald HamelbergJ Andrew McCammon
Aug 31, 2004·Nature Structural & Molecular Biology·Magnus Wolf-WatzDorothee Kern
Jan 22, 2005·Journal of Medicinal Chemistry·Adrian L GillHarren Jhoti
May 5, 2005·Journal of the American Chemical Society·Nilesh K Banavali, Benoît Roux
Oct 4, 2005·Journal of Computational Chemistry·David A CaseRobert J Woods
Dec 24, 2005·Angewandte Chemie·Martin VogtherrHarald Schwalbe
Feb 1, 1958·Proceedings of the National Academy of Sciences of the United States of America·D E Koshland
Apr 12, 2006·Physical Review Letters·Giovanni BussiMichele Parrinello
Jan 16, 2007·Journal of Molecular Biology·Paul C WhitfordJosé N Onuchic
Nov 9, 2007·Proceedings of the National Academy of Sciences of the United States of America·Jeffrey A HansonHaw Yang
Nov 15, 2007·Proceedings of the National Academy of Sciences of the United States of America·Karunesh Arora, Charles L Brooks
Nov 21, 2007·Nature·Katherine A Henzler-WildmanDorothee Kern
Dec 7, 2007·PLoS Computational Biology·S Bassi
May 9, 2008·Structure·Jörg GsponerMichele Vendruscolo
Dec 11, 2008·Journal of the American Chemical Society·Anna BerteottiMichele Parrinello
Dec 26, 2008·Proceedings of the National Academy of Sciences of the United States of America·Yibing ShanDavid E Shaw
Apr 14, 2009·Current Opinion in Structural Biology·John L KlepeisDavid E Shaw

❮ Previous
Next ❯

Citations

Nov 10, 2014·The Journal of Chemical Physics·Stefan M GiovanStephen D Levene
Dec 31, 2015·Current Opinion in Structural Biology·José Ramón López-Blanco, Pablo Chacón
Jan 7, 2015·Journal of Biomolecular Structure & Dynamics·Jianzhong ChenWeiliang Zhu
Nov 26, 2015·The Journal of Physical Chemistry. B·Mariana Bunoro Batista, Leandro Martinez
Nov 5, 2015·Biophysical Journal·Fabian Zeller, Martin Zacharias
May 27, 2015·Journal of Computer-aided Molecular Design·Hulya UnanMustafa Tekpinar
May 24, 2017·The Journal of Physical Chemistry. B·Ritaban HalderBiman Jana
Dec 21, 2019·Journal of Biomolecular Structure & Dynamics·Jianzhong ChenWeiliang Zhu
Feb 25, 2017·Intrinsically Disordered Proteins·Shelly DeForteVladimir N Uversky
Mar 1, 2016·National Science Review·Tingting LiuHualiang Jiang
Feb 27, 2021·The Journal of Physical Chemistry. B·Catherine Ghosh, Biman Jana
Nov 13, 2020·Journal of Chemical Information and Modeling·Jordi Juárez-JiménezJulien Michel
Oct 11, 2017·Journal of Chemical Theory and Computation·Parimal Kar, Michael Feig
Oct 16, 2019·The Journal of Physical Chemistry. B·Ritaban Halder, Biman Jana
Jun 28, 2019·The Journal of Physical Chemistry. B·Guido Todde, Ran Friedman
Oct 15, 2021·Journal of Chemical Theory and Computation·Baswanth Oruganti, Ran Friedman

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.