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A theoretical study on the molecular determinants of the affibody protein ZAbeta3 bound to an amyloid beta peptide.
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.ORCID iD: 0000-0001-9035-7086
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.ORCID iD: 0000-0002-1763-9383
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2015 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 17, no 26, 16886-16893 p.Article in journal (Refereed) Published
Abstract [en]

Amyloid beta (A beta) peptides are small cleavage products of the amyloid precursor protein. Aggregates of A beta peptides are thought to be linked with Alzheimer's and other neurodegenerative diseases. Strategies aimed at inhibiting amyloid formation and promoting A beta clearance have been proposed and investigated in in vitro experiments and in vivo therapies. A recent study indicated that a novel affibody protein Z(A beta 3), which binds to an A beta 40 monomer with a binding affinity of 17 nM, is able to prevent the aggregation of A beta 40. However, little is known about the energetic contribution of each residue in Z(A beta 3) to the formation of the (Z(A beta 3))(2):A beta complex. To address this issue, we carried out unbiased molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area calculations. Through the per-residue decomposition scheme, we identified that the van der Waals interactions between the hydrophobic residues of (Z(A beta 3))(2) and those at the exterior and interior faces of A beta are the main contributors to the binding of (Z(A beta 3))(2) to A beta. Computational alanine scanning identified 5 hot spots, all residing in the binding interface and contributing to the binding of (Z(A beta 3))(2) to A beta through the hydrophobic effect. In addition, the amide hydrogen bonds in the 4-strand beta-sheet and the pi-pi stacking were also analyzed. Overall, our study provides a theoretical basis for future experimental improvement of the Z(A beta 3) peptide binding to A beta.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2015. Vol. 17, no 26, 16886-16893 p.
National Category
Physical Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-170676DOI: 10.1039/c5cp00615eISI: 000356874000028PubMedID: 26060853Scopus ID: 2-s2.0-84934344084OAI: oai:DiVA.org:kth-170676DiVA: diva2:840262
Funder
Swedish Foundation for Strategic Research , SSF RB13-0192
Note

QC 20150707

Available from: 2015-07-07 Created: 2015-07-03 Last updated: 2017-12-04Bibliographically 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)
Opponent
Supervisors
Note

QC 20170516

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

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Sun, XianqiangÅgren, Hans

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