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Free Energy Profile and Kinetics for Coupled Folding and Binding of the Intrinsically Disordered Protein p53 with MDM2
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH).
KTH, School of Engineering Sciences (SCI), Mechanics, Structural Mechanics.ORCID iD: 0000-0002-3875-927X
Structural Biology and NMR Laboratory, Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen.
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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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Intrinsically disordered proteins (IDPs) exert their functions by binding to partner proteins via a complex process that includes coupled folding and binding. Motivated by that inhibiting the binding of the IDP p53 to its partner MDM2 has become a promising strategy for drug design and that understanding of this process poses a most significant challenging task, we present an atomistic level simulation of the coupled folding and binding process linking the IDP p53 to MDM2. Using bias-exchange metadynamics (BE-MetaD) and infrequent metadynamics (InMetaD) we estimate the binding free energy, the unbinding rate and the binding rate. By analyzing the stable intermediates, we uncover the role of nonnative interactions played in the p53-MDM2 binding/unbinding process. We use a three-state model to describe the whole binding/unbinding process and to obtain the corresponding rate constants. Our work shows that the binding of p53 favors an induced fit mechanism which proceeds in a stepwise fashion. In general, InMetaD gave consistent results with BE-MetaD in terms of binding mechanism and intermediates, proving the robustness of our studies of the p53-MDM2 system using metadynamics. The results contribute to the in-depth understanding for the coupled folding and binding process that is needed for the design of MDM2 inhibitors.

Keywords [en]
p53-MDM2, free energy landscape, kinetics, bias-exchange metadynamics, infrequent metadynamics
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:kth:diva-251311OAI: oai:DiVA.org:kth-251311DiVA, id: diva2:1314972
Note

QC 20190619

Available from: 2019-05-10 Created: 2019-05-10 Last updated: 2020-05-07Bibliographically approved
In thesis
1. Computational Studies of Protein-ligand Systems Using Enhanced Sampling Methods
Open this publication in new window or tab >>Computational Studies of Protein-ligand Systems Using Enhanced Sampling Methods
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis focuses on studies of protein-ligand systems using enhanced sampling methods. In chapter I, I give a brief introduction to the time-scale problem and some enhanced sampling methods. In chapter II, the basics of MD simulation are reviewed. In chapter III, the theoretical backgrounds of umbrella sampling, bias-exchange metadynamics and infrequent metadynamics are presented. In chapter IV, the 5 papers included in this thesis are summarized. In paper 1, we studied the relationship between the antibacterial activities of antimicrobial peptides and their aggregation propensities. We found that an increasing aggregation propensity increases the free energy cost of peptide embedding into the bacterial membrane and decreases antibacterial activity. In paper 2, we employed the umbrella sampling approach to obtain the free energy landscape of Pittsburgh compound-B penetrating into the core binding sites of amyloid βfibrils. Our study suggested that, for the design of probes binding to fibril like proteins, other than the binding affinity, the dynamics of probes in the fibrils should also be considered. In paper 3, we studied the coupled folding and binding process of the intrinsically disordered protein p53 to MDM2 with bias-exchange metadynamics and infrequent metadynamics. We reconstructed the free energy landscape and built a kinetic network for this process. In paper 4, we studied the binding modes of ASEM with a chimera structure of α7 nicotinic acetylcholine receptor with well-tempered metadynamics. We found that an important residue, Trp53, can significantly affect the stabilities of the binding modes. In paper 5, we proposed an efficient method to estimate the transition times of rare events in biomolecular systems. In chapter V, I present a conclusion of this thesis and propose an outlook related to the selection of collective variables for enhanced sampling methods.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2019. p. 58
Series
TRITA-CBH-FOU ; 34
Keywords
molecular dynamics, enhanced sampling, protein-ligand interactions, umbrella sampling, metadynamics
National Category
Natural Sciences
Research subject
Theoretical Chemistry and Biology
Identifiers
urn:nbn:se:kth:diva-251025 (URN)
Public defence
2019-06-05, FP41, Roslagstullsbacken 33, Byggnad 1, floor 4, AlbaNova, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

QC 2019-05-10

Available from: 2019-05-10 Created: 2019-05-08 Last updated: 2019-05-10Bibliographically approved
2. 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)
Opponent
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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Zhou, YangGuanglin, KuangTu, Yaoquan

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