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Prediction and Validation of Protein Intermediate States from Structurally Rich Ensembles and Coarse-Grained Simulations
KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.ORCID iD: 0000-0001-8354-0253
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Protein conformational changes are at the heart of cell functions, from signaling to ion transport. However, the transient nature of the intermediates along transition pathways hampers their experimental detection, making the underlying mechanisms elusive. Here, we retrieve dynamic information on the actual transition routes from Principal Component Analysis (PCA) of structurally-rich ensembles and, in combination with coarse-grained simulations, explore the conformational landscapes of five well-studied proteins. Modeling them as elastic networks in a hybrid Elastic-Network Brownian Dynamics simulation (eBDIMS), we generate trajectories connecting stable end-states that spontaneously sample the crystallographic motions, predicting the structures of known intermediates along thepaths. We also show that the explored non-linear routes can delimit the lowest energy passages between end-states sampled by atomistic molecular dynamics. The integrative methodology presented here provides a powerful framework to extract and expand dynamic pathway information from the Protein Data Bank, as well as to validate sampling methods in general. 

National Category
Structural Biology
Identifiers
URN: urn:nbn:se:kth:diva-187252OAI: oai:DiVA.org:kth-187252DiVA: diva2:929439
Note

QC 20160518

Available from: 2016-05-18 Created: 2016-05-18 Last updated: 2016-05-18Bibliographically approved
In thesis
1. Elucidating the Gating Mechanism of Cys-Loop Receptors
Open this publication in new window or tab >>Elucidating the Gating Mechanism of Cys-Loop Receptors
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cys-loop receptors are membrane proteins that are key players for the fast synaptic neurotransmission. Their ion transport initiates new nerve signals after activation by small agonist molecules, but this function is also highly sensitive to allosteric modulation by a number of compounds such as anesthetics, alcohol or anti-parasitic agents. For a long time, these modulators were believed to act primarily on the membrane, but the availability of high- resolution structures has made it possible to identify several binding sites in the transmembrane domains of the ion channels. It is known that ligand binding in the extracellular domain causes a conformational earthquake that interacts with the transmembrane domain, which leads to channel opening. The investigations carried out in this thesis aim at understanding the connection between ligand binding and channel opening.

I present new models of the mammalian GABAA receptor based on the eukaryotic structure GluCl co-crystallized with an anti-parasitic agent, and show how these models can be used to study receptor-modulator interactions. I also show how removal of the bound modulator leads to gradual closing of the channel in molecular dynamics simulations. In contrast, simulations of the receptor with both the agonist and the modulator remain stable in an open-like conformation. This makes it possible to extract several key interactions, and I propose mechanisms for how the extracellular domain motion is initiated. The rapid increase in the number of cys-loop receptor structures the last few years has further made it possible to use principal component analysis (PCA) to create low-dimensional descriptions of the conformational landscape. By performing PCA on the crystal structure ensemble, I have been able to divide the structures into functional clusters and sample the transitions between them using various sampling methods.

The studies presented in this thesis contribute to our understanding of the gating mechanism and the functional clustering of the cys-loop receptor structures, which both are important to design new allosteric modulator drugs that influence the channel function, in particular to treat neurological disorders.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2016. 72 p.
Series
TRITA-FYS, ISSN 0280-316X ; 2016:26
Keyword
ion channel, gating, simulation, molecular dynamics, receptor, cys-loop, modelling
National Category
Biophysics
Research subject
Theoretical Chemistry and Biology; Biological Physics
Identifiers
urn:nbn:se:kth:diva-187230 (URN)978-91-7729-009-4 (ISBN)
Public defence
2016-06-13, sal F3, Lindstedtsvägen 26, Stockholm, 14:00 (English)
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Supervisors
Note

QC 20160518

Available from: 2016-05-18 Created: 2016-05-18 Last updated: 2016-05-20Bibliographically approved

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