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Coupled Folding and Binding of the Intrinsically Disordered AICD Peptide in the Presence of the Fe65-PTB2 Protein
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.ORCID iD: 0000-0002-8662-373X
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(English)Article in journal (Refereed) Submitted
Abstract [en]

Intrinsically disordered proteins (IDPs) exert important cellular functions. Many IDPs that are partially or completely disordered in free states fold into well-defined tertiary structures upon binding to their targets, an association process involving coupled folding and binding. Although many biophysical and computational approaches have been applied to study coupled folding and binding reactions over the past decade, an atomic-level description of the binding of IDPs and the underlying mechanisms still represents a major challenge. Here, we present results of atomistic simulations of a natively unfolded peptide AICD binding to its target Fe65-PTB2. By bias-exchange metadynamics we computed a three-dimensional free-energy landscape for the binding process and identified several local minima corresponding to distinct intermediate states. The associated free energy is in good agreement with experimental results. By kinetic Monte Carlo simulations, we obtained two possible paths for AICD binding to Fe65-PTB2 that both confirm that the identified intermediates are on-path. We described the binding process with atomistic details, and found that the partially folded AICD peptide first approaches the Fe65-PTB2 protein to form different diffusion encounter complexes, which then evolve through multiple intermediates to the final native state. The binding of AICD proceeds via a kinetic divide-and-conquer strategy by which AICD folds in a stepwise fashion. We propose that the interaction of AICD with the target takes place via an induced fit mechanism. 

National Category
Physical Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-207096OAI: oai:DiVA.org:kth-207096DiVA: diva2:1095747
Note

QC 20170602

Available from: 2017-05-15 Created: 2017-05-15 Last updated: 2017-06-02Bibliographically approved
In thesis
1. Computational Studies of Structures and Binding Properties of Protein-Ligand Complexes
Open this publication in new window or tab >>Computational Studies of Structures and Binding Properties of Protein-Ligand Complexes
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Proteins are dynamic structural entities that are involved in many biophysical processes through molecular interactions with their ligands. Protein-ligand interactions are of fundamental importance for computer-aided drug discovery. Due to the fast development in computer technologies and theoretical methods, computational studies are by now able to provide atomistic-level description of structures, thermodynamic and dynamic properties of protein-ligand systems, and are becoming indispensable in understanding complicated biomolecular systems. In this dissertation, I have applied molecular dynamic (MD) simulations combined with several state of the art free-energy calculation methodologies, to understand structures and binding properties of several protein-ligand systems.

The dissertation consists of six chapters. In the first chapter, I present a brief introduction to classical MD simulations, to recently developed methods for binding free energy calculations, and to enhanced sampling of configuration space of biological systems. The basic features, including the Hamiltonian equations, force fields, integrators, thermostats, and barostats, that contribute to a complete MD simulation are described in chapter 2. In chapter 3, two classes of commonly used algorithms for estimating binding free energies are presented. I highlight enhanced sampling approaches in chapter 4, with a special focus on replica exchange MD simulations and metadynamics, as both of them have been utilized in my work presented in the chapter thereafter. In chapter 5, I outlined the work in the 5 papers included in the thesis. In paper I and II, I applied, respectively, the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) and alchemical free energy calculation methods to identify the molecular determinant of the affibody protein ZAb3 bound to an amyloid b peptide, and to investigate the binding profile of the positive allosteric modulator NS-1738 with the α7 acetylcholine-binding protein (α7-AChBP protein); in paper III and VI, unbiased MD simulations were integrated with the well-tempered metadynamics approach, with the aim to reveal the mechanism behind the higher selectivity of an antagonist towards corticotropin-releasing factor receptor-1 (CRF1R) than towards CRF2R, and to understand how the allosteric modulation induced by a sodium ion is propagated to the intracellular side of the d-opioid receptor; in the last paper, I proved the structural heterogeneity of the intrinsically disordered AICD peptide, and then employed the bias-exchange metadynamics and kinetic Monte Carlo techniques to understand the coupled folding and binding of AICD to its receptor Fe65-PTB2. I finally proposed that the interactions between AICD and Fe65-PTB2 take place through an induced-fit mechanism. In chapter 6, I made a short conclusion of the work, with an outlook of computational simulations of biomolecular systems.

Place, publisher, year, edition, pages
Stockholm, Sweden: KTH Royal Institute of Technology, 2017. 73 p.
Series
TRITA-BIO-Report, ISSN 1654-2312 ; 2017:13
National Category
Theoretical Chemistry
Research subject
Theoretical Chemistry and Biology
Identifiers
urn:nbn:se:kth:diva-207100 (URN)978-91-7729-421-4 (ISBN)
Public defence
2017-06-02, FB52, AlbaNova University Center, Stockholm, 10:00 (English)
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Note

QC 20170516

Available from: 2017-05-16 Created: 2017-05-15 Last updated: 2017-05-16Bibliographically approved

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