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      Conformational Flexibility Differentiates Naturally Occurring Bet v 1 Isoforms

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          Abstract

          The protein Bet v 1 represents the main cause for allergic reactions to birch pollen in Europe and North America. Structurally homologous isoforms of Bet v 1 can have different properties regarding allergic sensitization and Th2 polarization, most likely due to differential susceptibility to proteolytic cleavage. Using NMR relaxation experiments and molecular dynamics simulations, we demonstrate that the initial proteolytic cleavage sites in two naturally occurring Bet v 1 isoforms, Bet v 1.0101 (Bet v 1a) and Bet v 1.0102 (Bet v 1d), are conformationally flexible. Inaccessible cleavage sites in helices and strands are highly flexible on the microsecond-millisecond time scale, whereas those located in loops display faster nanosecond-microsecond flexibility. The data consistently show that Bet v 1.0102 is more flexible and conformationally heterogeneous than Bet v 1.0101. Moreover, NMR hydrogen-deuterium exchange measurements reveal that the backbone amides in Bet v 1.0102 are significantly more solvent exposed, in agreement with this isoform’s higher susceptibility to proteolytic cleavage. The differential conformational flexibility of Bet v 1 isoforms, along with the transient exposure of inaccessible sites to the protein surface, may be linked to proteolytic susceptibility, representing a potential structure-based rationale for the observed differences in Th2 polarization and allergic sensitization.

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          Molecular dynamics and protein function.

          M Karplus, J Kuriyan (2005)
          A fundamental appreciation for how biological macromolecules work requires knowledge of structure and dynamics. Molecular dynamics simulations provide powerful tools for the exploration of the conformational energy landscape accessible to these molecules, and the rapid increase in computational power coupled with improvements in methodology makes this an exciting time for the application of simulation to structural biology. In this Perspective we survey two areas, protein folding and enzymatic catalysis, in which simulations have contributed to a general understanding of mechanism. We also describe results for the F(1) ATPase molecular motor and the Src family of signaling proteins as examples of applications of simulations to specific biological systems.
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            Generalized Langevin equation approach for atom/solid-surface scattering: General formulation for classical scattering off harmonic solids

            S. Adelman (1976)
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              Protein Binding Pocket Dynamics.

              Antonia Stank, Daria Kokh, Jonathan C. Fuller … (2016)
              The dynamics of protein binding pockets are crucial for their interaction specificity. Structural flexibility allows proteins to adapt to their individual molecular binding partners and facilitates the binding process. This implies the necessity to consider protein internal motion in determining and predicting binding properties and in designing new binders. Although accounting for protein dynamics presents a challenge for computational approaches, it expands the structural and physicochemical space for compound design and thus offers the prospect of improved binding specificity and selectivity. A cavity on the surface or in the interior of a protein that possesses suitable properties for binding a ligand is usually referred to as a binding pocket. The set of amino acid residues around a binding pocket determines its physicochemical characteristics and, together with its shape and location in a protein, defines its functionality. Residues outside the binding site can also have a long-range effect on the properties of the binding pocket. Cavities with similar functionalities are often conserved across protein families. For example, enzyme active sites are usually concave surfaces that present amino acid residues in a suitable configuration for binding low molecular weight compounds. Macromolecular binding pockets, on the other hand, are located on the protein surface and are often shallower. The mobility of proteins allows the opening, closing, and adaptation of binding pockets to regulate binding processes and specific protein functionalities. For example, channels and tunnels can exist permanently or transiently to transport compounds to and from a binding site. The influence of protein flexibility on binding pockets can vary from small changes to an already existent pocket to the formation of a completely new pocket. Here, we review recent developments in computational methods to detect and define binding pockets and to study pocket dynamics. We introduce five different classes of protein pocket dynamics: (1) appearance/disappearance of a subpocket in an existing pocket; (2) appearance/disappearance of an adjacent pocket on the protein surface in the direct vicinity of an already existing pocket; (3) pocket breathing, which may be caused by side-chain fluctuations or backbone or interdomain vibrational motion; (4) opening/closing of a channel or tunnel, connecting a pocket inside the protein with solvent, including lid motion; and (5) the appearance/disappearance of an allosteric pocket at a site on a protein distinct from an already existing pocket with binding of a ligand to the allosteric binding site affecting the original pocket. We suggest that the class of pocket dynamics, as well as the type and extent of protein motion affecting the binding pocket, should be factors considered in choosing the most appropriate computational approach to study a given binding pocket. Furthermore, we examine the relationship between pocket dynamics classes and induced fit, conformational selection, and gating models of ligand binding on binding kinetics and thermodynamics. We discuss the implications of protein binding pocket dynamics for drug design and conclude with potential future directions for computational analysis of protein binding pocket dynamics.
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                Author and article information

                Contributors
                Fatima Ferreira: Role: Academic Editor
                Hans Brandstetter: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 03 June 2017
                Publication date Collection: June 2017
                Volume: 18
                Issue: 6
                Electronic Location Identifier: 1192
                Affiliations
                [1 ]Institute of Organic Chemistry & Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80/82, A-6020 Innsbruck, Austria; sarina.grutsch@ 123456uibk.ac.at (S.G.); linda.ahammer@ 123456uibk.ac.at (L.A.)
                [2 ]Institute of Inorganic and Theoretical Chemistry & Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80/82, A-6020 Innsbruck, Austria; julian.fuchs@ 123456uibk.ac.at (J.E.F.); anna.kamenik@ 123456uibk.ac.at (A.S.K.)
                Author notes
                [* ]Correspondence: klaus.liedl@ 123456uibk.ac.at (K.R.L.); martin.tollinger@ 123456uibk.ac.at (M.T.); Tel.: +43-512-507-57100 (K.R.L.); +43-512-507-57730 (M.T.)
                [†]

                These authors contributed equally to this work.

                [‡]

                Current Address: Department of Medicinal Chemistry, Boehringer Ingelheim RCV GmbH & Co KG, Doktor-Boehringer-Gasse 5-11, A-1120 Vienna, Austria.

                Article
                Publisher ID: ijms-18-01192
                DOI: 10.3390/ijms18061192
                PMC ID: 5486015
                PubMed ID: 28587205
                SO-VID: 23a78388-54b5-4320-82af-6743c5e9e58e
                Copyright © © 2017 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 28 April 2017
                Date accepted : 30 May 2017
                Categories
                Subject: Article

                ScienceOpen disciplines: Molecular biology
                Keywords: allergens,proteolytic processing,allergic sensitization,allergen structure,flexibility
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: allergens, proteolytic processing, allergic sensitization, allergen structure, flexibility

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