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Computational Studies of Structures and Binding Properties of Protein-Ligand Complexes
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.ORCID iD: 0000-0002-8662-373X
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. , p. 73
Series
TRITA-BIO-Report, ISSN 1654-2312 ; 2017:13
National Category
Theoretical Chemistry
Research subject
Theoretical Chemistry and Biology
Identifiers
URN: urn:nbn:se:kth:diva-207100ISBN: 978-91-7729-421-4 (print)OAI: oai:DiVA.org:kth-207100DiVA, id: diva2:1095752
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
List of papers
1. A theoretical study on the molecular determinants of the affibody protein ZAbeta3 bound to an amyloid beta peptide.
Open this publication in new window or tab >>A theoretical study on the molecular determinants of the affibody protein ZAbeta3 bound to an amyloid beta peptide.
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2015 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 17, no 26, p. 16886-16893Article 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
National Category
Physical Chemistry
Identifiers
urn:nbn:se:kth:diva-170676 (URN)10.1039/c5cp00615e (DOI)000356874000028 ()26060853 (PubMedID)2-s2.0-84934344084 (Scopus ID)
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
2. Theoretical study of the binding profile of an allosteric modulator NS-1738 with a chimera structure of the alpha 7 nicotinic acetylcholine receptor
Open this publication in new window or tab >>Theoretical study of the binding profile of an allosteric modulator NS-1738 with a chimera structure of the alpha 7 nicotinic acetylcholine receptor
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2016 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 18, no 40, p. 28003-28009Article in journal (Refereed) Published
Abstract [en]

Potentiation of the function of the alpha 7 nicotinic acetylcholine receptor (alpha 7-nAChR) is believed to provide a possible way for the treatment of cholinergic system dysfunctions such as Alzheimer's disease and schizophrenia. Positive allosteric modulators (PAMs) are able to augment the peak current response of the endogenous agonist of alpha 7-nAChR by binding to some allosteric sites. In this study, the binding profile of a potent type I PAM, NS-1738, with a chimera structure (termed alpha 7-AChBP) constructed from the extracellular domain of alpha 7-nAChR and an acetylcholine binding protein was investigated with molecular docking, molecular dynamics simulation, and free energy calculation methods. We found that NS-1738 could bind to three allosteric sites of alpha 7-AChBP, namely, the top pocket, the vestibule pocket and the agonist sub-pocket. NS-1738 has moderate binding affinities (-6.76 to -9.15 kcal mol(-1)) at each allosteric site. The urea group is critical for binding and can form hydrogen-bond interactions with the protein. The bulky trifluoromethyl group also has a great impact on the binding modes and binding affinities. We believe that our study provides valuable insight into the binding profiles of type I PAMs with alpha 7-nAChR and is helpful for the development of novel PAMs.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2016
National Category
Biochemistry and Molecular Biology
Research subject
Theoretical Chemistry and Biology
Identifiers
urn:nbn:se:kth:diva-196385 (URN)10.1039/c6cp02278b (DOI)000385180600033 ()27711412 (PubMedID)2-s2.0-84991672104 (Scopus ID)
Note

QC 20161124

Available from: 2016-11-24 Created: 2016-11-14 Last updated: 2017-05-17Bibliographically approved
3. Residues remote from the binding pocket control the antagonist selectivity towards the corticotropin-releasing factor receptor-1
Open this publication in new window or tab >>Residues remote from the binding pocket control the antagonist selectivity towards the corticotropin-releasing factor receptor-1
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2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, p. 8066-Article in journal (Refereed) Published
Abstract [en]

The corticotropin releasing factors receptor-1 and receptor-2 (CRF1R and CRF2R) are therapeutic targets for treating neurological diseases. Antagonists targeting CRF1R have been developed for the potential treatment of anxiety disorders and alcohol addiction. It has been found that antagonists targeting CRF1R always show high selectivity, although CRF1R and CRF2R share a very high rate of sequence identity. This has inspired us to study the origin of the selectivity of the antagonists. We have therefore built a homology model for CRF2R and carried out unbiased molecular dynamics and well-tempered metadynamics simulations for systems with the antagonist CP-376395 in CRF1R or CRF2R to address this issue. We found that the side chain of Tyr(6.63) forms a hydrogen bond with the residue remote from the binding pocket, which allows Tyr(6.63) to adopt different conformations in the two receptors and results in the presence or absence of a bottleneck controlling the antagonist binding to or dissociation from the receptors. The rotameric switch of the side chain of Tyr356(6.63) allows the breaking down of the bottleneck and is a perquisite for the dissociation of CP-376395 from CRF1R.

Keywords
Protein-Coupled Receptors, Beta(2)-Adrenergic Receptor, Molecular-Dynamics, Conformations, Pharmacology, Sensitivity, Activation, Kinetics, Pathway
National Category
Biological Sciences Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-160743 (URN)10.1038/srep08066 (DOI)000348435800001 ()25628267 (PubMedID)
Funder
Swedish National Infrastructure for Computing (SNIC), SNIC2013-26-31 SNIC2013-1-236
Note

QC 20150302

Available from: 2015-03-02 Created: 2015-02-27 Last updated: 2017-12-04Bibliographically approved
4. Propagation of the Allosteric Modulation Induced by Sodium in the delta-Opioid Receptor
Open this publication in new window or tab >>Propagation of the Allosteric Modulation Induced by Sodium in the delta-Opioid Receptor
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2017 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 23, no 19, p. 4615-4624Article in journal (Refereed) Published
Abstract [en]

Allosteric sodium in the helix bundle of a G protein-coupled receptor (GPCR) can modulate the receptor activation on the intracellular side. This phenomenon has confounded the GPCR community for decades. In this work, we present a theoretical model that reveals the mechanism of the allosteric modulation induced by sodium in the delta-opioid receptor. We found that the allosteric sodium ion exploits a distinct conformation of the key residue Trp2746.48 to propagate the modulation to helices 5 and 6, which further transmits along the helices and regulates their positions on the intracellular side. This mechanism is supported by subsequent functional assays. Remarkably, our results highlight the contrast between the allosteric effects towards two GPCR partners, the G protein and b-arrestin, as indicated by the fact that the allosteric modulation initiated by the sodium ion significantly affects the b-arrestin recruitment, while it alters the G protein signaling only moderately. We believe that the mechanism revealed in this work can be used to explain allosteric effects initiated by sodium in other GPCRs since the allosteric sodium is highly conserved across GPCRs. 

Place, publisher, year, edition, pages
John Wiley & Sons, 2017
National Category
Physical Chemistry
Identifiers
urn:nbn:se:kth:diva-207095 (URN)10.1002/chem.201605575 (DOI)
Funder
Swedish National Infrastructure for Computing (SNIC), SNIC2015-16-10; SNIC2015-1-396
Note

QC 20170519

Available from: 2017-05-15 Created: 2017-05-15 Last updated: 2017-11-29Bibliographically approved
5. Coupled Folding and Binding of the Intrinsically Disordered AICD Peptide in the Presence of the Fe65-PTB2 Protein
Open this publication in new window or tab >>Coupled Folding and Binding of the Intrinsically Disordered AICD Peptide in the Presence of the Fe65-PTB2 Protein
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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:nbn:se:kth:diva-207096 (URN)
Note

QC 20170602

Available from: 2017-05-15 Created: 2017-05-15 Last updated: 2017-06-02Bibliographically approved

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