MP:PD—a data base of internal packing densities, internal packing defects and internal waters of helical membrane proteins

The membrane protein packing database (MP:PD) (http://proteinformatics.charite.de/mppd) is a database of helical membrane proteins featuring internal atomic packing densities, cavities and waters. Membrane proteins are not tightly packed but contain a considerable number of internal cavities that differ in volume, polarity and solvent accessibility as well as in their filling with internal water. Internal cavities are supposed to be regions of high physical compressibility. By serving as mobile hydrogen bonding donors or acceptors, internal waters likely facilitate transition between different functional states. Despite these distinct functional roles, internal cavities of helical membrane proteins are not well characterized, mainly because most internal waters are not resolved by crystal structure analysis. Here we combined various computational biophysical techniques to characterize internal cavities, reassign positions of internal waters and calculate internal packing densities of all available helical membrane protein structures and stored them in MP:PD. The database can be searched using keywords and entries can be downloaded. Each entry can be visualized in Provi, a Jmol-based protein viewer that provides an integrated display of low energy waters alongside membrane planes, internal packing density, hydrophobic cavities and hydrogen bonds.

[1]  Patrick Scheerer,et al.  Effect of channel mutations on the uptake and release of the retinal ligand in opsin , 2012, Proceedings of the National Academy of Sciences.

[2]  Zsuzsanna Dosztányi,et al.  TMDET: web server for detecting transmembrane regions of proteins by using their 3D coordinates , 2005, Bioinform..

[3]  James U Bowie,et al.  Shifting hydrogen bonds may produce flexible transmembrane helices , 2012, Proceedings of the National Academy of Sciences.

[4]  M. Sanner,et al.  Reduced surface: an efficient way to compute molecular surfaces. , 1996, Biopolymers.

[5]  C. Sander,et al.  An effective solvation term based on atomic occupancies for use in protein simulations , 1993 .

[6]  Barry Honig,et al.  Helical packing patterns in membrane and soluble proteins. , 2004, Biophysical journal.

[7]  Kristian Rother,et al.  Molecular packing and packing defects in helical membrane proteins. , 2005, Biophysical journal.

[8]  Stefan Günther,et al.  Hydrogen-bonding and packing features of membrane proteins: functional implications. , 2008, Biophysical journal.

[9]  Jose A. Caro,et al.  Cavities determine the pressure unfolding of proteins , 2012, Proceedings of the National Academy of Sciences.

[10]  J. Thornton,et al.  Buried waters and internal cavities in monomeric proteins , 1994, Protein science : a publication of the Protein Society.

[11]  Volkhard Helms,et al.  Druggability of dynamic protein-protein interfaces. , 2012, Current pharmaceutical design.

[12]  Jürgen Sühnel,et al.  HBexplore - a new tool for identifying and analysing hydrogen bonding patterns in biological macromolecules , 1996, Comput. Appl. Biosci..

[13]  Mark R. Chance,et al.  Structural waters define a functional channel mediating activation of the GPCR, rhodopsin , 2009, Proceedings of the National Academy of Sciences.

[14]  G. Hong,et al.  Nucleic Acids Research , 2015, Nucleic Acids Research.

[15]  Mark Gerstein,et al.  Calculations of protein volumes: sensitivity analysis and parameter database , 2002, Bioinform..

[16]  K. Henrick,et al.  Inference of macromolecular assemblies from crystalline state. , 2007, Journal of molecular biology.

[17]  W. Hubbell,et al.  High-pressure EPR reveals conformational equilibria and volumetric properties of spin-labeled proteins , 2011, Proceedings of the National Academy of Sciences.

[18]  M. Kimmel,et al.  Conflict of interest statement. None declared. , 2010 .

[19]  J. Thornton,et al.  PQS: a protein quaternary structure file server. , 1998, Trends in biochemical sciences.

[20]  K. Gerwert,et al.  Proton transfer via a transient linear water-molecule chain in a membrane protein , 2011, Proceedings of the National Academy of Sciences.

[21]  Kristian Rother,et al.  Inhomogeneous molecular density: reference packing densities and distribution of cavities within proteins , 2003, Bioinform..

[22]  Klaus Gerwert,et al.  Functional waters in intraprotein proton transfer monitored by FTIR difference spectroscopy , 2006, Nature.

[23]  Andrei L. Lomize,et al.  Anisotropic Solvent Model of the Lipid Bilayer. 1. Parameterization of Long-Range Electrostatics and First Solvation Shell Effects , 2011, J. Chem. Inf. Model..

[24]  Robert Preissner,et al.  Voronoi cell: New method for allocation of space among atoms: Elimination of avoidable errors in calculation of atomic volume and density , 1997, J. Comput. Chem..

[25]  H Luecke,et al.  Structure of bacteriorhodopsin at 1.55 A resolution. , 1999, Journal of molecular biology.

[26]  Charles L. Brooks,et al.  Community-wide assessment of GPCR structure modelling and ligand docking: GPCR Dock 2008 , 2009, Nature Reviews Drug Discovery.

[27]  Brian W Matthews,et al.  A review about nothing: Are apolar cavities in proteins really empty? , 2009, Protein science : a publication of the Protein Society.

[28]  David S. Goodsell,et al.  The RCSB Protein Data Bank: new resources for research and education , 2012, Nucleic Acids Res..

[29]  Sameer Velankar,et al.  PDBe: Protein Data Bank in Europe , 2009, Nucleic Acids Res..

[30]  Andrei L. Lomize,et al.  Anisotropic Solvent Model of the Lipid Bilayer. 2. Energetics of Insertion of Small Molecules, Peptides, and Proteins in Membranes , 2011, J. Chem. Inf. Model..

[31]  G. Klebe,et al.  Identification and mapping of small-molecule binding sites in proteins: computational tools for structure-based drug design. , 2002, Farmaco.

[32]  Patrick Barth,et al.  Naturally evolved G protein-coupled receptors adopt metastable conformations , 2012, Proceedings of the National Academy of Sciences.

[33]  Hyeon Joo,et al.  OPM database and PPM web server: resources for positioning of proteins in membranes , 2011, Nucleic Acids Res..

[34]  Dániel Kozma,et al.  PDBTM: Protein Data Bank of transmembrane proteins after 8 years , 2012, Nucleic Acids Res..

[35]  Leonardo Pardo,et al.  The Role of Internal Water Molecules in the Structure and Function of the Rhodopsin Family of G Protein‐Coupled Receptors , 2007, Chembiochem : a European journal of chemical biology.

[36]  Gwyndaf Evans,et al.  Membrane protein structure determination — The next generation , 2014, Biochimica et biophysica acta.

[37]  J Hermans,et al.  Hydrophilicity of cavities in proteins , 1996, Proteins.

[38]  Gebhard F. X. Schertler,et al.  The structural basis of agonist-induced activation in constitutively active rhodopsin , 2011, Nature.

[39]  R Nussinov,et al.  A set of van der Waals and coulombic radii of protein atoms for molecular and solvent‐accessible surface calculation, packing evaluation, and docking , 1998, Proteins.

[40]  B. Matthews.  Proteins under pressure , 2012, Proceedings of the National Academy of Sciences.

[41]  S. White,et al.  Biophysical dissection of membrane proteins , 2009, Nature.

[42]  G. Otting,et al.  NMR identification of hydrophobic cavities with ow water occupancies in protein structures using small gas molecules , 1997, Nature Structural Biology.