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Title: Orientation Preferences of Backbone Secondary Amide Functional Groups in Peptide Nucleic Acid Complexes: Quantum Chemical Calculations Reveal an Intrinsic Preference of Cationic D-Amino Acid-Based Chiral PNA Analogues for the P-form

Authors:
 [1];  [2]
  1. University of Heidelberg
  2. ORNL
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE Laboratory Directed Research and Development (LDRD) Program
OSTI Identifier:
950446
DOE Contract Number:
DE-AC05-00OR22725
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biophysical Journal; Journal Volume: 92; Journal Issue: 3
Country of Publication:
United States
Language:
English

Citation Formats

Topham, Christopher, and Smith, Jeremy C. Orientation Preferences of Backbone Secondary Amide Functional Groups in Peptide Nucleic Acid Complexes: Quantum Chemical Calculations Reveal an Intrinsic Preference of Cationic D-Amino Acid-Based Chiral PNA Analogues for the P-form. United States: N. p., 2007. Web. doi:10.1529/biophysj.105.079723.
Topham, Christopher, & Smith, Jeremy C. Orientation Preferences of Backbone Secondary Amide Functional Groups in Peptide Nucleic Acid Complexes: Quantum Chemical Calculations Reveal an Intrinsic Preference of Cationic D-Amino Acid-Based Chiral PNA Analogues for the P-form. United States. doi:10.1529/biophysj.105.079723.
Topham, Christopher, and Smith, Jeremy C. Thu . "Orientation Preferences of Backbone Secondary Amide Functional Groups in Peptide Nucleic Acid Complexes: Quantum Chemical Calculations Reveal an Intrinsic Preference of Cationic D-Amino Acid-Based Chiral PNA Analogues for the P-form". United States. doi:10.1529/biophysj.105.079723.
@article{osti_950446,
title = {Orientation Preferences of Backbone Secondary Amide Functional Groups in Peptide Nucleic Acid Complexes: Quantum Chemical Calculations Reveal an Intrinsic Preference of Cationic D-Amino Acid-Based Chiral PNA Analogues for the P-form},
author = {Topham, Christopher and Smith, Jeremy C},
abstractNote = {},
doi = {10.1529/biophysj.105.079723},
journal = {Biophysical Journal},
number = 3,
volume = 92,
place = {United States},
year = {Thu Feb 01 00:00:00 EST 2007},
month = {Thu Feb 01 00:00:00 EST 2007}
}
  • Geometric descriptions of nonideal interresidue hydrogen bonding and backbone-base water bridging in the minor groove are established in terms of polyamide backbone carbonyl group orientation from analyses of residue junction conformers in experimentally determined peptide nucleic acid (PNA) complexes. Two types of interresidue hydrogen bonding are identified in PNA conformers in heteroduplexes with nucleic acids that adopt A-like base pair stacking. Quantum chemical calculations on the binding of a water molecule to an O2 base atom in glycine-based PNA thymine dimers indicate that junctions modeled with P-form backbone conformations are lower in energy than a dimer comprising the predominant conformationmore » observed in A-like helices. It is further shown in model systems that PNA analogs based on D-lysine are better able to preorganize in a conformation exclusive to P-form helices than is glycine-based PNA. An intrinsic preference for this conformation is also exhibited by positively charged chiral PNA dimers carrying 3-amino-D-alanine or 4-aza-D-leucine residue units that provide for additional rigidity by side-chain hydrogen bonding to the backbone carbonyl oxygen. Structural modifications stabilizing P-form helices may obviate the need for large heterocycles to target DNA pyrimidine bases via PNADNA-PNA triplex formation. Quantum chemical modeling methods are used to propose candidate PNA Hoogsteen strand designs.« less
  • PNA is a pseudopeptide DNA mimic in which the natural nucleobases have been retained, but the backbone consists of {ital N}-(2-aminoethyl)glycine units to which the nucleobases are attached via methylene carbonyl linkers. The finding that PNA forms Warson-Crick-like helices with complementary DNA, RNA or PNA combined with the fact PNA is held together by amide bonds has made PNA of interest as a model for a primordial genetic material. Furthermore, the PNA backbone is achiral, while preferred chirality can be induced in PNA-PNA double helices by attached chiral ligands, thereby providing a new way of {open_quote}{open_quote}chiral amplification.{close_quote}{close_quote} Finally, it hasmore » been demonstrated that PNA-template directed synthesis of RNA and PNA is feasible. {copyright} {ital 1996 American Institute of Physics.}« less
  • Hybridization of a radiolabeled single-stranded DNA oligonucleotide with its single-stranded complement in vivo has not yet been convincingly demonstrated. A contributing factor may be unfavorable in vivo properties of the phosphodiester and phosphorothioate DNAs. Peptide nucleic acid (PNA) oligomers have been reported to possess in vivo properties more suitable for radiopharmaceutical applications. We have radiolabeled an amine-derivatized 15-base PNA oligomer with {sup 99m}Tc through a modified MAG{sub 3} chelator. The ability of the PNA to hybridize in vitro with its complement appeared to be unimpaired after conjugation and radiolabeling. Size-exclusion, high-performance liquid chromatography (HPLC) analysis of 37{degree}C serum after 24more » hr of incubation showed the radiolabel to be present predominately as labeled PNA with indications of labeled serum proteins and a low molecular weight catabolite. Whole-body clearance in mice was rapid, with 50% of the label eliminated in about 2 hr. After 2.5 hr, the highest uptake (kidneys) was only 1.5% of the injected dose/g; less than 0.07%/g was present in all sampled tissues at 24 hr. To evaluate in vivo hybridization, beads were implanted subcutaneously in both thighs of normal mice. In the left thigh only, the beads were conjugated with complementary single-stranded PNA. At 23 hr following intraperitoneal administration of the labeled PNA, the left/right thigh radioactivity ratio was 6:1. Whole-body images at this time showed only bladder, kidneys and the left thigh. Unlike the radiolabeled DNAs investigated in this laboratory, {sup 99m}Tc-PNA displays stability and pharmacokinetic properties suitable for eventual use as radiopharmaceuticals.« less
  • The hydration process of side chain analogue molecules differs from that of the actual amino acid side chains in peptides and proteins owing to the effects of the peptide backbone on the aqueous solvent environment. A recent molecular simulation study has provided evidence that all nonpolar side chains, attached to a short peptide backbone, are considerably less hydrophobic than the free side chain analogue molecules. In contrast to this, the hydrophilicity of the polar side chains is hardly affected by the backbone. To analyze the origin of these observations, we here present a molecular simulation study on temperature dependent solvationmore » free energies of nonpolar and polar side chains attached to a short peptide backbone. The estimated solvation entropies and enthalpies of the various amino acid side chains are compared with existing side chain analogue data. The solvation entropies and enthalpies of the polar side chains are negative, but in absolute magnitude smaller compared with the corresponding analogue data. The observed differences are large; however, owing to a nearly perfect enthalpy-entropy compensation, the solvation free energies of polar side chains remain largely unaffected by the peptide backbone. We find that a similar compensation does not apply to the nonpolar side chains; while the backbone greatly reduces the unfavorable solvation entropies, the solvation enthalpies are either more favorable or only marginally affected. This results in a very small unfavorable free energy cost, or even free energy gain, of solvating the nonpolar side chains in strong contrast to solvation of small hydrophobic or nonpolar molecules in bulk water. The solvation free energies of nonpolar side chains have been furthermore decomposed into a repulsive cavity formation contribution and an attractive dispersion free energy contribution. We find that cavity formation next to the peptide backbone is entropically favored over formation of similar sized nonpolar side chain cavities in bulk water, in agreement with earlier work in the literature on analysis of cavity fluctuations at nonpolar molecular surfaces. The cavity and dispersion interaction contributions correlate quite well with the solvent accessible surface area of the nonpolar side chains attached to the backbone. This correlation however is weak for the overall solvation free energies owing to the fact that the cavity and dispersion free energy contributions are almost exactly cancelling each other.« less