Abstract
NMR data obtained by solid state NMR from anisotropic samples are used as orientational constraints in molecular dynamics simulations for determining the structure and dynamics of the PGLa peptide within a membrane environment. For the simulation the recently developed molecular dynamics with orientational constraints technique (MDOC) is used. This method introduces orientation dependent pseudo-forces into the COSMOS-NMR force field. Acting during a molecular dynamics simulation these forces drive molecular rotations, re-orientations and folding in such a way that the motional time-averages of the tensorial NMR properties are consistent with the experimentally measured NMR parameters. This MDOC strategy does not depend on the initial choice of atomic coordinates, and is in principle suitable for any flexible and mobile kind of molecule; and it is of course possible to account for flexible parts of peptides or their side-chains. MDOC has been applied to the antimicrobial peptide PGLa and a related dimer model. With these simulations it was possible to reproduce most NMR parameters within the experimental error bounds. The alignment, conformation and order parameters of the membrane-bound molecule and its dimer were directly derived with MDOC from the NMR data. Furthermore, this new approach yielded for the first time the distribution of segmental orientations with respect to the membrane and the order parameter tensors of the dimer systems. It was demonstrated the deuterium splittings measured at the peptide to lipid ratio of 1/50 are consistent with a membrane spanning orientation of the peptide.
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References
Afonin S (2010) KIT Karlsruhe, IBG, Private communication
Bechinger B, Zasloff M, Opella SJ (1998) Structure and dynamics of the antibiotic peptide PGLa in membranes by solution and solid-state nuclear magnetic resonance spectroscopy. Biophys J 74:981–987
Bürck J, Roth S, Wadhwani P, Afonin S, Kanithasen N, Strandberg E, Ulrich AS (2008) Conformation and membrane orientation of amphiphilic helical peptides by oriented circular dichroism. Biophys J 95:3872–3881. doi:10.1529/biophysj.108.136085
Evans DJ, Morris GP (1990) Mechanics of nonequilibrium liquids. Academic Press, London
Leontiadou H, Mark AE, Marrink SJ (2006) Antimicrobial peptides in action. J Am Chem Soc 128:12156–12161. doi:10.1021/ja062927q
Sternberg U, Möllhoff M (2001) Molecular mechanics with fluctuating atomic charges—a new force field with a semiempirical charge calculation. J Mol Model 7:90–102
Sternberg U, Koch F-T, Bräuer M, Kunert M, Anders E (2001) Molecular mechanics for zinc complexes with fluctuating atomic charges. J Mol Model 7:54–64
Sternberg U, Witter R, Ulrich AS (2004) 3D structure elucidation using NMR chemical shifts. In: Advances in solid state NMR studies of materials and polymers: a special volume dedicated to Isao Ando, vol 52. Annual reports on NMR spectroscopy. pp 53–104
Sternberg U, Witter R, Ulrich AS (2007) All-atom molecular dynamics simulations using orientational constraints from anisotropic NMR samples. J Biomol NMR 38:23–39
Sternberg U, Klipfel M, Grage SL, Witter R, Ulrich AS (2009) Calculation of fluorine chemical shift tensors for the interpretation of oriented F-19-NMR spectra of gramicidin A in membranes. Phys Chem Chem Phys 11:7048–7060
Strandberg E, Wadhwani P, Tremouilhac P, Durr UHN, Ulrich AS (2006) Solid-state NMR analysis of the PGLa peptide orientation in DMPC bilayers: structural fidelity of H-2-labels versus high sensitivity of F-19-NMR. Biophys J 90:1676–1686
Strandberg E, Tremouilhac P, Wadhwani P, Ulrich AS (2009) Synergistic transmembrane insertion of the heterodimeric PGLa/magainin 2 complex studied by solid-state NMR. Biochim Biophys Acta 1788:1667–1679. doi:10.1016/j.bbamem.2008.12.018
Tieleman DP, Berendsen HJ, Sansom MS (2001) Voltage-dependent insertion of alamethicin at phospholipid/water and octane/water interfaces. Biophys J 80:331–346
Tremouilhac P, Strandberg E, Wadhwani P, Ulrich AS (2006) Conditions affecting the re-alignment of the antimicrobial peptide PGLa in membranes as monitored by solid state 2H-NMR. Biochim Biophys Acta 1758:1330–1342. doi:10.1016/j.bbamem.2006.02.029
Ulmschneider JP, Smith JC, Ulmschneider MB, Ulrich AS, Strandberg E (2012) Reorientation and dimerization of the membrane-bound antimicrobial peptide PGLa from microsecond all-atom MD simulations. Biophys J 103:472–482. doi:10.1016/j.bpj.2012.06.040
Verlet L (1967) Computer “experiments” on classical fluids. I. Thermodynamical properties of Lennard-Jones molecules. Phys Rev 159:98–103
Wakamatsu K, Takeda A, Tachi T, Matsuzaki K (2002) Dimer structure of magainin 2 bound to phospholipid vesicles. Biopolymers 64:314–327
Witter R, Seyfart L, Greiner G, Reissmann S, Weston J, Anders E, Sternberg U (2002) Structure determination of a pseudotripeptide zinc complex with the COSMOS-NMR force field and DFT methods. J Biomol NMR 24:277–289. doi:10.1023/a:1021625231147
Witter R, Sternberg U, Hesse S, Kondo T, Koch FT, Ulrich AS (2006) C-13 chemical shift constrained crystal structure refinement of cellulose I-alpha and its verification by NMR anisotropy experiments. Macromolecules 39:6125–6132. doi:10.1021/ma052439n
Witter R, Möllhoff M, Koch FT, Sternberg U (2015) Fast atomic charge calculation for implementation into a polarizable force field: application to an ion channel protein. J Chem (in press)
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Gratefully we appreciate European Social Fund, Estonia Science Foundation (ESF), Tallinn University of Technology for funding project MTT68 and support from Karlsruhe Institute of Technology.
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Sternberg, U., Witter, R. Molecular dynamics simulations on PGLa using NMR orientational constraints. J Biomol NMR 63, 265–274 (2015). https://doi.org/10.1007/s10858-015-9983-y
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DOI: https://doi.org/10.1007/s10858-015-9983-y