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      Conformational Changes in the Epidermal Growth Factor Receptor: Role of the Transmembrane Domain Investigated by Coarse-Grained MetaDynamics Free Energy Calculations

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          Abstract

          The epidermal growth factor receptor (EGFR) is a dimeric membrane protein that regulates key aspects of cellular function. Activation of the EGFR is linked to changes in the conformation of the transmembrane (TM) domain, brought about by changes in interactions of the TM helices of the membrane lipid bilayer. Using an advanced computational approach that combines Coarse-Grained molecular dynamics and well-tempered MetaDynamics (CG-MetaD), we characterize the large-scale motions of the TM helices, simulating multiple association and dissociation events between the helices in membrane, thus leading to a free energy landscape of the dimerization process. The lowest energy state of the TM domain is a right-handed dimer structure in which the TM helices interact through the N-terminal small-X 3-small sequence motif. In addition to this state, which is thought to correspond to the active form of the receptor, we have identified further low-energy states that allow us to integrate with a high level of detail a range of previous experimental observations. These conformations may lead to the active state via two possible activation pathways, which involve pivoting and rotational motions of the helices, respectively. Molecular dynamics also reveals correlation between the conformational changes of the TM domains and of the intracellular juxtamembrane domains, paving the way for a comprehensive understanding of EGFR signaling at the cell membrane.

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          Molecular dynamics with coupling to an external bath

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            Canonical sampling through velocity-rescaling

            We present a new molecular dynamics algorithm for sampling the canonical distribution. In this approach the velocities of all the particles are rescaled by a properly chosen random factor. The algorithm is formally justified and it is shown that, in spite of its stochastic nature, a quantity can still be defined that remains constant during the evolution. In numerical applications this quantity can be used to measure the accuracy of the sampling. We illustrate the properties of this new method on Lennard-Jones and TIP4P water models in the solid and liquid phases. Its performance is excellent and largely independent on the thermostat parameter also with regard to the dynamic properties.
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              Escaping free-energy minima

              We introduce a novel and powerful method for exploring the properties of the multidimensional free energy surfaces of complex many-body systems by means of a coarse-grained non-Markovian dynamics in the space defined by a few collective coordinates.A characteristic feature of this dynamics is the presence of a history-dependent potential term that, in time, fills the minima in the free energy surface, allowing the efficient exploration and accurate determination of the free energy surface as a function of the collective coordinates. We demonstrate the usefulness of this approach in the case of the dissociation of a NaCl molecule in water and in the study of the conformational changes of a dialanine in solution.
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                Author and article information

                Journal
                J Am Chem Soc
                J. Am. Chem. Soc
                ja
                jacsat
                Journal of the American Chemical Society
                American Chemical Society
                0002-7863
                1520-5126
                26 July 2016
                24 August 2016
                : 138
                : 33
                : 10611-10622
                Affiliations
                []Department of Biochemistry, University of Oxford , South Parks Road, Oxford OX1 3QU, U.K.
                []CERMAV, Université Grenoble Alpes and CNRS , BP 53, F-38041 Grenoble Cedex 9, France
                [§ ]Università della Svizzera Italiana (USI), Faculty of Informatics, Institute of Computational Science − Center for Computational Medicine in Cardiology , via G. Buffi 13, CH-6900 Lugano, Switzerland
                []Department of Pharmacy, University of Naples “Federico II” , via D. Montesano 49, I-80131 Naples, Italy
                Author notes
                Article
                10.1021/jacs.6b05602
                5010359
                27459426
                ba0c3ffe-81c7-4f3d-bdbd-64f03457bf31
                Copyright © 2016 American Chemical Society

                This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.

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                ja6b05602
                ja-2016-056029

                Chemistry
                Chemistry

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