The aim of the proposed research is to determine the three-dimensional structure (by x-ray diffraction of single crystals) of a number of peptides (10-30 residues) that perform a variety of functions such as ion transport, analgesia, toxic, antitoxic and antibiotic by means of single crystal x-ray diffraction analysis. These crystals are composed of molecules containing light atoms only, C, N, O and H. The method of solution will be direct phase determination using the tangent formula and a variety of auxiliary formulas. Linear peptides mediating ion transport through cell membranes, particularly those in the class of peptaibophol antibiotics, are being emphasized currently. They are characterized by their length (up to 20 residues), a number of Aib residues (alpha aminoisobutyric acid) and one or more Pro residues that interfere with alpha-helix formation. The immediate goal is to establish the conformation of neighboring peptide molecules in the crystal. Structures of Leu-zervamicin in three separate crystal forms have been determined to 0.9 A resolution that give very suggestive information concerning ion channels and gating. Structure analysis has begun on antiamoebin, a related ionophore. Crystallizations are in progress for zervamicin IIB (the major component of the zervamicin family). The ultimate goal is to establish the shape and function of ion channels on an atomic scale and gating mechanisms to correlate them with measured electrical conductances. This knowledge should be very useful in the whole field of physiological ion transport through voltage dependent membranes. Further goals are to continue to establish characteristics of peptide helices, such as helix aggregation, water insertion into hydrophobic helices, facile transitions between 3(l0) and alpha-helices, bends in helices, polar surfaces on largely or completely apolar helices, all of which provide supporting information for ion transport processes. X-ray quality single crystals are on hand.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM030902-21
Application #
6525698
Study Section
Special Emphasis Panel (NSS)
Program Officer
Flicker, Paula F
Project Start
1982-08-01
Project End
2004-05-31
Budget Start
2002-09-01
Budget End
2004-05-31
Support Year
21
Fiscal Year
2002
Total Cost
$57,450
Indirect Cost
Name
U.S. Naval Research Laboratory
Department
Type
DUNS #
020060658
City
Washington
State
DC
Country
United States
Zip Code
20375
Karle, Isabella L; Huang, Lulu; Venkateshwarlu, Punna et al. (2009) SUBTLE CONTROL IN SOLUTION AND CRYSTAL STRUCTURES WITH WEAK HYDROGEN BONDS: THE UNUSUAL PROFILE OF DIMETHYL 3, 12-DIOXO-7, 8 DITHIA 4, 11-DIAZABICYCLO[12.2.2]OCTADECA-1(16), 14, 17-TRIENE 5, 10-DICARBOXYLATE (TDA1). Heterocycles 79:471-486
Huang, Lulu; Massa, Lou; Karle, Isabella et al. (2009) Calculation of strong and weak interactions in TDA1 and RangDP52 by the kernel energy method. Proc Natl Acad Sci U S A 106:3664-9
Karle, Isabella L; Ranganathan, Darshan; Kumar, Mittapalli Gopi et al. (2008) Design, synthesis, conformational and membrane ion transport studies of proline-adamantane hybrid cyclic depsipeptides. Biopolymers 89:471-8
Karle, Isabella L; Venkateshwarlu, P; Ranganathan, S (2006) A robust hybrid peptide crystal formed with weak hydrogen bonds. Biopolymers 84:502-7
Karle, I L; Ranganathan, D (2005) An asymmetric conformation of 1,3,5-benzene tricarbonyl [Aib4OMe]3. J Pept Res 65:65-70
Roy, Rituparna S; Karle, Isabella L; Raghothama, S et al. (2004) Alpha,beta hybrid peptides: a polypeptide helix with a central segment containing two consecutive beta-amino acid residues. Proc Natl Acad Sci U S A 101:16478-82
Karle, I L; Prasad, S; Balaram, P (2004) A combined extended and helical backbone for Boc-(Ala-Leu-Ac7c-)2-OMe. J Pept Res 63:175-80
Ravindra, Gudihal; Ranganayaki, Rappal S; Raghothama, Srinivasa et al. (2004) Two novel hexadepsipeptides with several modified amino acid residues isolated from the fungus Isaria. Chem Biodivers 1:489-504
Karle, Isabella L; Gopi, Hosahudya N; Balaram, Padmanabhan (2003) Crystal structure of a hydrophobic 19-residue peptide helix containing three centrally located D amino acids. Proc Natl Acad Sci U S A 100:13946-51
Aravinda, Subrayashastry; Shamala, Narayanaswamy; Das, Chittaranjan et al. (2003) Aromatic-aromatic interactions in crystal structures of helical peptide scaffolds containing projecting phenylalanine residues. J Am Chem Soc 125:5308-15

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