A convenient method for determining cyclic peptide conformation from 1D 1H-NMR information.

A rapid and convenient method for determining the backbone conformation of cyclic peptides results from the combination of 1D 1H NMR information and molecular modeling. phi Angle torsional constraints calculated from 3JHN.H alpha coupling constants are used to determine the position of multiple-welled potential energy penalty functions that are imposed on the force field used in the structure refinement (Amber* with GB/SA solvation model). Monte Carlo searches and minimizations lead to a collection of structures that are clustered by backbone similarity and then filtered according to hydrogen-bonding constraints determined by the chemical shift temperature dependencies of the amide protons. This approach was applied to five cyclic peptides whose structures had been determined previously using more extensive 2D NMR techniques, and the importance of the torsional, H-bonding, and solvation restraints were assessed. For the four peptides that adopt a predominant conformation, this method reproduced the reported structures closely; lack of convergence for the fifth structure reflected the multiple backbone conformations that this macrocycle adopts.

[1]  T. Gadek,et al.  Structural studies of potent constrained RGD peptides , 1992 .

[2]  H. Kessler,et al.  Peptide flexibility and calculations of an ensemble of molecules , 1994 .

[3]  V. Bystrov.  Spin—spin coupling and the conformational states of peptide systems , 1976 .

[4]  L. Gierasch,et al.  Design of biologically active, conformationally constrained GnRH antagonists , 1990, Proteins.

[5]  Paul A. Bartlett,et al.  CAVEAT: A program to facilitate the design of organic molecules , 1994, J. Comput. Aided Mol. Des..

[6]  Horst Kessler,et al.  Peptide conformations. 46. Conformational analysis of a superpotent cytoprotective cyclic somatostatin analog , 1988 .

[7]  G. Wagner.  Principles of Multidimensional NMR , 1994 .

[8]  C. Humblet,et al.  Design, synthesis and solution structure of a renin inhibitor Structural constraints from NOE, and homonuclear and heteronuclear coupling constants combined with distance geometry calculations , 1992, FEBS letters.

[9]  M. Lipton,et al.  Cyclic hexapeptides and chimeric peptides as mimics of tendamistat , 1994 .

[10]  D F Mierke,et al.  Coupling constants again: Experimental restraints in structure refinement , 1994, J. Comput. Aided Mol. Des..

[11]  W. C. Still,et al.  Semianalytical treatment of solvation for molecular mechanics and dynamics , 1990 .

[12]  Peter A. Kollman,et al.  Can the Lennard–Jones 6‐12 function replace the 10‐12 form in molecular mechanics calculations? , 1991 .

[13]  C. E. Peishoff,et al.  Conformations of Arg-Gly-Asp containing heterodetic cyclic peptides: solution and crystal studies , 1992 .

[14]  A. Doherty,et al.  The solution structure of a cyclic endothelin antagonist, BQ‐123, based on 1H–1H and 13H–1H three bond oupling constants , 1992, FEBS letters.

[15]  R. Hosur,et al.  Conformation of Biological Molecules , 1982 .

[16]  G. Wagner.  NMR INVESTIGATIONS OF PROTEIN STRUCTURE , 1990 .

[17]  S. P. Fodor,et al.  Applications of combinatorial technologies to drug discovery. 1. Background and peptide combinatorial libraries. , 1994, Journal of medicinal chemistry.

[18]  C. E. Peishoff,et al.  Investigation of conformational specificity at GPIIb/IIIa: evaluation of conformationally constrained RGD peptides. , 1992, Journal of medicinal chemistry.

[19]  Horst Kessler,et al.  Conformation and Biological Activity of Cyclic Peptides , 1982 .

[20]  G. Chang,et al.  Macromodel—an integrated software system for modeling organic and bioorganic molecules using molecular mechanics , 1990 .

[21]  H. Matter,et al.  Structures, Dynamics, and Biological Activities of 15 Cyclic Hexapeptide Analogs of the .alpha.-Amylase Inhibitor Tendamistat (HOE 467) in Solution , 1995 .

[22]  M. Bock,et al.  Cyclic hexapeptide oxytocin antagonists. Potency-, selectivity-, and solubility-enhancing modifications. , 1990, Journal of medicinal chemistry.

[23]  S. P. Fodor,et al.  Applications of combinatorial technologies to drug discovery. 2. Combinatorial organic synthesis, library screening strategies, and future directions. , 1994, Journal of medicinal chemistry.

[24]  Jonathan A. Ellman,et al.  SIMULTANEOUS SOLID-PHASE SYNTHESIS OF BETA -TURN MIMETICS INCORPORATING SIDE-CHAIN FUNCTIONALITY , 1994 .

[25]  H. Kessler,et al.  Peptide Conformation from Coupling Constants: Scalar Couplings as Restraints in MD Simulations , 1992 .

[26]  H. Kessler,et al.  Multidimensional NMR Spectroscopy of Peptides , 1994 .

[27]  H. Kessler,et al.  Coupling constants and hydrogen bonds as experimental restraints in a distance geometry refinement protocol. , 2009, International journal of peptide and protein research.

[28]  W. DeGrado,et al.  Template-Constrained Cyclic Peptides: Design of High-Affinity Ligands for GPIIb/IIIa , 1994 .

[29]  W. Guida,et al.  Probing the conformational space available to inhibitors in the thermolysin active site using Monte Carlo/energy minimization techniques , 1992 .