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Mechanistic insights into peptide and ligand binding of the ATAD2-bromodomain via atomistic simulations disclosing a role of induced fit and conformational selection
KTH, School of Engineering Sciences (SCI), Mechanics, Structural Mechanics.ORCID iD: 0000-0002-3875-927X
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.ORCID iD: 0000-0002-3138-820X
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2018 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 20, no 36, p. 23222-23232Article in journal (Refereed) Published
Abstract [en]

ATAD2 has emerged as a promising bromodomain (BRD)-containing therapeutic drug target in multiple human cancers. However, recent druggability assessment studies predicted ATAD2's BRD as a target 'difficult to drug' because its binding pocket possesses structural features that are unfeasible for ligand binding. Here, by using all-atom molecular dynamics simulations and an advanced metadynamics method, we demonstrate a dynamic view of the binding pocket features which can hardly be obtained from the "static" crystal data. The most important features disclosed from our simulation data, include: (1) a distinct 'open-to-closed' conformational switch of the ZA loop region in the context of peptide or ligand binding, akin to the induced fit mechanism of molecular recognition, (2) a dynamic equilibrium of the BC loop "in" and "out" conformations, highlighting a role in the conformational selection mechanism for ligand binding, and (3) a new binding region identified distal to the histone-binding pocket that might have implications in bromodomain biology and in inhibitor development. Moreover, based on our simulation results, we propose a model for an "auto-regulatory" mechanism of ATAD2's BRD for histone binding. Overall, the results of this study will not only have implications in bromodomain biology but also provide a theoretical basis for the discovery of new ATAD2's BRD inhibitors.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2018. Vol. 20, no 36, p. 23222-23232
Keywords [en]
AAA protein, ATAD2 protein, human, DNA binding protein, ligand, peptide, binding site, chemistry, conformation, human, molecular dynamics, ATPases Associated with Diverse Cellular Activities, Binding Sites, DNA-Binding Proteins, Humans, Ligands, Molecular Conformation, Molecular Dynamics Simulation, Peptides
National Category
Atom and Molecular Physics and Optics
Identifiers
URN: urn:nbn:se:kth:diva-236425DOI: 10.1039/c8cp03860kISI: 000447370600005PubMedID: 30137066Scopus ID: 2-s2.0-85053795262OAI: oai:DiVA.org:kth-236425DiVA, id: diva2:1258990
Note

QC 20181026

Available from: 2018-10-26 Created: 2018-10-26 Last updated: 2020-05-07Bibliographically approved
In thesis
1. Modeling Kinetics of Protein-Ligand Systems
Open this publication in new window or tab >>Modeling Kinetics of Protein-Ligand Systems
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Protein-ligand interactions dominate many life activities and are crucial for thedevelopment of tracers for diagnosing diseases and drugs for treating diseases.For protein-ligand interactions, the binding affinity is conventionally believedto be the most important indicator. However, there is increasing evidencethat the binding affinity alone is not sufficient for providing comprehensiveinformation about protein-ligand interactions. Kinetics, which describes theduration of the interactions and is closely related to the interaction mechanism,is considered as important as, or even more important than, the binding affinityin the study of the mechanisms of protein-ligand interactions.Although kinetics parameters of a protein-ligand system can be measuredexperimentally, the underlying molecular mechanism for the kinetics is difficultto reveal by experiment, which is, however, essential for understanding theorigin of the kinetics and for the rational design of drugs or tracers. In the lastdecade, computer simulations have emerged as a powerful tool for studying biomolecularsystems. Computer simulation methods have also been developedfor modeling kinetics of protein-ligand systems.In this thesis, I explored computer simulations for modeling kinetics propertiesof four different protein-ligand systems. In paper I, I studied the relationshipbetween the ligand binding and conformational changes of the ATAD2-BRD protein. In paper II, I investigated the free energy profile for the coupledfolding and binding of the intrinsically disordered protein p53 with MDM2and calculated the rate constants for the binding and unbinding processes. Inpaper III, I revealed the unbinding paths of the PET tracer ASEM from the  a7-nAChR, calculated the unbinding rate, and explored a way of how to findthe key protein conformational changes strongly coupled to the ligand unbindingprocess. In paper IV, I further refined our methodology for finding theunbinding paths and clarified the unbinding mechanism of the metabolite ofraloxifene from the enzyme CYP3A4.

Abstract [sv]

Protein-ligandinteraktioner dominerar många livsaktiviteter och är avgörande för utvecklingen av spårare för att diagnostisera sjukdomar och läkemedel för behandling av sjukdomar. För protein-ligandinteraktioner antas konventionell bindningsaffinitet vara den viktigaste indikatorn. Det finns emellertid ökande bevis på att bindningsaffiniteten enbart inte är tillräcklig för att tillhandahålla omfattande information om protein-ligandinteraktioner. Kinetik, som beskriver varaktigheten på interaktioner och är nära besläktad med interaktionsmekanismen, anses vara så viktig som, eller ännu viktigare än bindningsaffiniteten i studien av mekanismerna för protein-ligandinteraktioner.

 

Även om kinetikparametrar i ett protein-ligandsystem kan mätas experimentellt är den underliggande molekylära mekanismen för kinetiken svår att avslöja genom experiment, vilket dock är väsentligt för att förstå kinetikens ursprung och för den rationella utformningen av läkemedel eller spårare . Under det senaste decenniet har datorsimuleringar framkommit som ett kraftfullt verktyg för att studera biomolekylära system. Datorsimuleringsmetoder har också utvecklats för att modellera kinetik för protein-ligandsystem.

 

I den här avhandlingen undersökte jag datorsimuleringar för modellering av kinetiska egenskaper hos fyra olika protein-ligandsystem. I papper I studerade jag sambandet mellan ligandbindningen och konformationella förändringar av ATAD2-BRD-proteinet. I papper II undersökte jag den fria energiprofilen för den kopplade vikningen och bindningen av det intrinsiskt störda proteinet p53-peptid med MDM2 och beräknade hastighetskonstanterna för bindnings- och bindningsförfarandena. I papper III avslöjade jag de bindande vägarna för PET-spåraren ASEM från α7-nAChR, beräknade bindningsgraden och utforskade ett sätt att hitta de viktiga proteinkonformationella förändringarna starkt kopplade till ligandbindningsprocessen. I papper IV förfinade jag ytterligare vår metod för att hitta de bindande vägarna och klargjorde den bindande mekanismen för metaboliten av raloxifen från enzymet CYP3A4.

Place, publisher, year, edition, pages
KTH Royal Institute of Technology, 2020. p. 57
Series
TRITA-CBH-FOU ; 2020:25
National Category
Theoretical Chemistry
Research subject
Theoretical Chemistry and Biology
Identifiers
urn:nbn:se:kth:diva-273146 (URN)978-91-7873-545-7 (ISBN)
Public defence
2020-06-03, https://kth-se.zoom.us/webinar/register/WN_ZxwH8-GQTFaTv9ifiiTsAA ​, Stockholm, 10:00 (English)
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Supervisors
Note

QC 2020-05-08

Available from: 2020-05-08 Created: 2020-05-07 Last updated: 2020-05-20Bibliographically approved

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