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Computational Studies of Protein-ligand Systems Using Enhanced Sampling Methods
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH).
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 [en]
molecular dynamics, enhanced sampling, protein-ligand interactions, umbrella sampling, metadynamics
National Category
Natural Sciences
Research subject
Theoretical Chemistry and Biology
Identifiers
URN: urn:nbn:se:kth:diva-251025OAI: oai:DiVA.org:kth-251025DiVA, id: diva2:1314290
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
List of papers
1. Activity of Antimicrobial Peptide Aggregates Decreases with Increased Cell Membrane Embedding Free Energy Cost
Open this publication in new window or tab >>Activity of Antimicrobial Peptide Aggregates Decreases with Increased Cell Membrane Embedding Free Energy Cost
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2018 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 57, no 18, p. 2606-2610Article in journal (Refereed) Published
Abstract [en]

Antimicrobial peptides (AMPs) are a promising alternative to antibiotics for mitigating bacterial infections, in light of increasing bacterial resistance to antibiotics. However, predicting, understanding, and controlling the antibacterial activity of AMPs remain a significant challenge. While peptide intramolecular interactions are known to modulate AMP antimicrobial activity, peptide intermolecular interactions remain elusive in their impact on peptide bioactivity. Herein, we test the relationship between AMP intermolecular interactions and antibacterial efficacy by controlling AMP intermolecular hydrophobic and hydrogen bonding interactions. Molecular dynamics simulations and Gibbs free energy calculations in concert with experimental assays show that increasing intermolecular interactions via interpeptide aggregation increases the energy cost for the peptide to embed into the bacterial cell membrane, which in turn decreases the AMP antibacterial activity. Our findings provide a route for predicting and controlling the antibacterial activity of AMPs against Gram-negative bacteria via reductions of intermolecular AMP interactions.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2018
National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-228427 (URN)10.1021/acs.biochem.8b00052 (DOI)000431927100008 ()29638118 (PubMedID)2-s2.0-85046780456 (Scopus ID)
Note

QC 20180529

Available from: 2018-05-29 Created: 2018-05-29 Last updated: 2019-05-10Bibliographically approved
2. Free Energy Profile for Penetration of Pittsburgh Compound-B into the Amyloid beta Fibril
Open this publication in new window or tab >>Free Energy Profile for Penetration of Pittsburgh Compound-B into the Amyloid beta Fibril
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2019 (English)In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 10, no 3, p. 1783-1790Article in journal (Refereed) Published
Abstract [en]

The amyloid beta (A beta) fibril is a hallmark of Alzheimer's disease (AD) and has therefore served as an important target for early diagnosis of AD. The Pittsburgh Compound-B (PiB) is one of the most famous positron emission tomography (PET) tracers commonly used for in vivo detection of A beta fibrils. Many theoretical studies have predicted the existence of various core binding sites with different microenvironments for probes binding to the A beta fibril. However, little attention has been devoted to how the probes actually penetrate into the different core binding sites. In this study, an integrated molecular modeling scheme is used to study the penetration of PiB into the core binding sites of the A beta(1-42) fibril structure recently obtained by cryogenic electron microscopy. We find that there are two core binding sites for PiB with dramatic differences in cavity size and microenvironment properties, and furthermore that the penetration of PiB into site-1 is energetically prohibitive, whereas the penetration into site 2 is much more favorable. Therefore, the binding capacity at site-2 may be larger than that at site-1 despite its lower binding affinity. Our results thus suggest that site-2 may be a major binding site for PiB binding to A beta fibril and emphasize the importance to adopt a full dynamical picture when studying tracer fibril binding problems in general, something that in turn can be used to guide the development of tracers with higher affinity and selectivity for the A beta fibril.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2019
Keywords
Amyloid beta fibril, binding sites, imaging agents, free energy profiles, molecular dynamics simulation, umbrella sampling
National Category
Neurosciences
Identifiers
urn:nbn:se:kth:diva-249893 (URN)10.1021/acschemneuro.8b00662 (DOI)000462259900081 ()30698013 (PubMedID)2-s2.0-85061903405 (Scopus ID)
Note

QC 20190424

Available from: 2019-04-24 Created: 2019-04-24 Last updated: 2019-05-10Bibliographically approved
3. Free Energy Profile and Kinetics for Coupled Folding and Binding of the Intrinsically Disordered Protein p53 with MDM2
Open this publication in new window or tab >>Free Energy Profile and Kinetics for Coupled Folding and Binding of the Intrinsically Disordered Protein p53 with MDM2
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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
p53-MDM2, free energy landscape, kinetics, bias-exchange metadynamics, infrequent metadynamics
National Category
Natural Sciences
Identifiers
urn:nbn:se:kth:diva-251311 (URN)
Note

QC 20190619

Available from: 2019-05-10 Created: 2019-05-10 Last updated: 2019-06-19Bibliographically approved
4. Characterization of the binding mode of the PET tracer [18F]ASEM to a chimera structure of the α7 nicotinic acetylcholine receptor
Open this publication in new window or tab >>Characterization of the binding mode of the PET tracer [18F]ASEM to a chimera structure of the α7 nicotinic acetylcholine receptor
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2017 (English)In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 7, no 32, p. 19787-19793Article in journal (Refereed) Published
Abstract [en]

The α7 nicotinic acetylcholine receptor (α7-nAChR) is assumed to be implicated in a variety of neurological disorders, such as schizophrenia and Alzheimer's disease (AD). The progress of these disorders can be studied through imaging α7-nAChR with positron emission tomography (PET). [18F]ASEM is a novel and potent α7-nAChR PET radioligand showing great promise in recent tests. However, the mechanism of the molecular interaction between [18F]ASEM and α7-nAChR is still unclear. In this paper, the binding profile of [18F]ASEM to a chimera structure of α7-nAChR was investigated with molecular docking, molecular dynamics, and metadynamics simulation methods. We found that [18F]ASEM binds at the same site as the crystallized agonist epibatidine but with a different binding mode. The dibenzo[b,d]thiophene ring has a different orientation compared to the pyridine ring of epibatidine and has van der Waals interactions with residues from loop C on one side and π-π stacking interaction with Trp53 on the other side. The conformation of Trp53 was found to have a great impact on the binding of [18F]ASEM. Six binding modes in terms of the side chain dihedral angles χ1 and χ2 of Trp53 were discovered by metadynamics simulation. In the most stable binding mode, Trp53 adopts a different conformation from that in the crystalline structure and has a rather favorable π-π stacking interaction with [18F]ASEM. We believe that these discoveries can be valuable for the development of novel PET radioligands.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2017
Keywords
Binding energy, Dihedral angle, Molecular dynamics, Neurodegenerative diseases, Positron emission tomography, Van der Waals forces, Alzheimer's disease, Crystalline structure, Metadynamics simulations, Molecular docking, Neurological disorders, Nicotinic acetylcholine receptors, Positron emission tomography (PET), Van Der Waals interactions, Bins
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-207402 (URN)10.1039/c7ra00496f (DOI)000399242100041 ()2-s2.0-85017176981 (Scopus ID)
Funder
Swedish Foundation for Strategic Research , RB13-0192Stockholm County Council, K1764-2013Swedish National Infrastructure for Computing (SNIC), m.2015-1-396
Note

QC 20170601

Available from: 2017-06-01 Created: 2017-06-01 Last updated: 2019-10-08Bibliographically approved
5. An Efficient Strategy for the Estimation of Rare Event Transition Times in Biomolecular Systems
Open this publication in new window or tab >>An Efficient Strategy for the Estimation of Rare Event Transition Times in Biomolecular Systems
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Studies of kinetics in biological systems are important for understanding functions of biomolecules and can provide valuable information for drug discovery. However, how to obtain the kinetics closely related to a rare event occurring in a biomolecular system from conventional unbiased molecular dynamics (MD) simulations remains a big challenge. Recently, an enhanced sampling method, namely infrequent metadynamics (InMetaD), has been developed and has the capability to recover the unbiased transition time from metadynamic runs. However, in this method a bias potential is deposited to the system at a low frequency, which often makes most of the computational time spend in waiting for the simulated system escaping from the initial state. Here we propose a strategy to achieve the same goal as InMetaD with increased efficiency. In this strategy, we first accelerate the occurring of a rare event using metadynamics simulations with a high bias deposition frequency, and subsequently restart the simulations at a time point before the rare event occurs, but with a low bias deposition frequency. Through combining these simulation data, the unbiased transition time can be recovered in the same way as in InMetaD. We applied this strategy to the studies of three systems including the conformational change of a small peptide, unfolding of a protein, and unbinding of an intrinsically disordered protein from its target. We show that our strategy can improve the efficiency in estimating the unbiased transition times in a very convenient way.

Keywords
enhanced sampling, infrequent metadynamics, kinetics, rare-event
National Category
Natural Sciences
Identifiers
urn:nbn:se:kth:diva-251310 (URN)
Note

QC 20190619

Available from: 2019-05-10 Created: 2019-05-10 Last updated: 2019-06-19Bibliographically approved

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