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Peptides and proteins in membranes
Andrei L.Lomize , Irina D.Pogozheva
This project includes developments of membrane protein structure databases and computational methods for modeling of peptides and proteins in the lipid bilayer.

Figure 1: Transmembrane protein positioned in the anisotropic environment of the lipid bilayer.

Anisotropic solvent model of the lipid bilayer

As a part of this project, we have developed a new computational method PPM (v 2.0) for simulations of small molecules, peptides and proteins in membranes. The method is based on a new universal solvation model for predicting transfer energies of macromolecules from water to an arbitrary isotropic solvent. The transfer energy is computed as a sum of the following terms: (a) a surface area-dependent contribution that describes solute-solvent interactions in the first solvation shell (van der Waals, H-bonding, and entropy of solvent); (b) long-range electrostatic energy of solute dipoles and ionized groups in a media, and (c) deionization penalty for ionizable groups in nonpolar environment. The first-shell contribution is described by linear dependencies of the energy on solvent bulk dielectric constant (ε) and empirical hydrogen bond acidity (α) and basicity (β) parameters. The electrostatic term is described by Block-Walker equation for dipoles and by a modified Born equation for ions. The parameters of the model were derived from fitting 1269 experimental transfer energies of nonpolar, polar and charged molecules from water to 19 organic solvents. An all-atom representation of a solute is combined with a continuum representation of a lipid bilayer as described by concentration of water and different lipid segments and profiles of parameters ε, α, and β. The polarity profiles were calculated for several artificial phospholipid bilayers based on the published distributions of volume fractions of lipid components obtained by X-ray and neutron scattering (Figure 1 A,B). The bilayer has a well defined "mid-polar" region (9 to 20 Å from the membrane center) with a steep gradient of all polarity parameters whose values depend on the lipid composition. This approach allows adjustment of polarity profiles for different types of biological membranes.

Figure 2: (A) Profiles of hydrogen bonding donor (α) and acceptor (β) capacity, solvatochromic polarizability parameter (π*), dielectric constant (ε), dielectric function F(ε), and volume fraction of non-polar media (HDC) along the membrane normal. Polarity parameters were calculated using distributions along the membrane normal of volume fractions of lipid components obtained by X-ray and neutron scattering for fluid DOPC bilayer (B, Kucerka et al., 2008 Biophys. J. 95: 2356–2367).

OPM and Membranome databases

OPM database provides 3D structures of transmembrane, monotopic and peripheral proteins optimized with respect to the lipid bilayer. The initial prototype of our new human Membranome database is currently under construction. It will provide annotations, classification, experimental structures and computational models of proteins, lipids, and small molecules that can be found in different types of cellular membranes (51) and distinct types of human cells (~500). At the first stage, it will provide annotated and verified data and 3D models only for single-spanning (bitopic) human proteins.

Figure 3: Experimental 3D structures of human bitopic proteins positioned in the lipid bilayer by the PPM 2.0: (A) monomer of monoamine oxidase A, 2z5x; (B) pentamer of phospholamban (1zll); (C) TM α-helices of integrin αIIb-β3 dimer (2k9j). Hydrophobic membrane boundaries are shown by blue (inner leaflet) and red (outer leaflet) balls.

Folding and association of α-helical peptides in membranes

A comprehensive quantitative model of folding, insertion and association of α-helical peptides in membranes is under development. It combines thermodynamic theory of helix-coil transition in membranes, empirical energy functions derived from protein engineering, and the new anisotropic solvent model of the lipid bilayer.

Related Publications

Kumar A., Lomize A., Jin K.K., Carlton D., Miller M.D., Jaroszewski L., Abdubek P., Astakhova T., Axelrod H. L., Chiu H.-J., Clayton T., Das D., et al
Open and closed conformations of two SpoIIAA-like proteins (YP_749275.1 and YP_001095227.1) provide insights into membrane association and ligand binding.
Acta Crystallogr, F66: doi: 10.1107/S1744309109042481 (2010)

Chi H.-J., Bakolitsa C., Skerra A., Lomize A., Carlton D., Miller M.D., Krishna S.S., Abdubek P., Astakhova T., Axelrod H. L., Clayton T., et al.,
Structure of the first representative of Pfam familyPF09410 (DUF2006) reveals a structural signature of the calycin superfamily that suggests a role in lipid metabolism.
Acta Crystallogr, F 66: doi:10.1107/S1744309109037749 (2010)

Lomize AL, Pogozheva ID, Lomize MA, Mosberg HI
The role of hydrophobic interactions in positioning of peripheral proteins in membranes
BMC Struct Biol, 7: 44 (2007)

Lomize MA, Lomize AL, Pogozheva ID, Mosberg HI
OPM: orientations of proteins in membranes database.
Bioinformatics, 22: 623-625 (2006)

Lomize AL, Pogozheva ID, Lomize MA, Mosberg HI
Positioning of proteins in membranes: a computational approach
Protein Sci., 15: 1318-1333 (2006)

Lomize AL, Pogozheva ID, Mosberg HI
Quantification of helix-helix binding affinities in micelles and lipid bilayers.
Protein Sci., 13: 2600-2612 (2004)

Lomize AL, Reibarkh MY, Pogozheva ID
Interatomic potentials and solvation parameters from protein engineering data for buried residues.
Protein Sci., 11: 1984-2000 (2002)

Lomize AL, Mosberg HI
Thermodynamic model of secondary structure for alpha-helical peptides and proteins.
Biopolymers., 42: 239-269 (1997)

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Design and synthesis of biologically active opioid peptides and peptidomimetics
Investigations of MOR and DOR trafficking and crosstalk
Development of mixed efficacy opioid ligands
Peptides and proteins in membranes
Homology modeling of GPCRs, important drug targets
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