title: Molecular Dynamics Study of Nitrogen-Pyramidalized Bicyclic β-Proline Oligomers: Length-Dependent Convergence to Organized Structures.
abstract: In this study, the solution structures of the homooligomers of a conformationally constrained bicyclic proline-type β-amino acid were studied by means of molecular dynamics (MD) calculations in explicit methanol and water using the umbrella sampling method. The ratio of trans-amide and cis-amide was estimated by NMR and the rotational barrier of the amide of acetylated bicyclic amino acid monomer was estimated by two-dimensional (2D) exchange spectroscopy (EXSY) or line-shape analysis. A bias potential was introduced with respect to the amide torsion angle ω to enhance conformational exchange including isomerization of amide bonds by lowering the rotation energy barrier. After determination of reweighting parameters to best reproduce the experimental results of the monomer amide, the free energy profile around the amide torsion angle ω was obtained from the MD trajectory by reweighting of the biased probability density. The MD simulation results support the existence of invertomers of nitrogen-pyramidalized amide. Furthermore, extended structures with a high fraction of trans-amide conformation appear to be increasingly stabilized as the oligomer is elongated, both in methanol and in water. Our conformational analysis of natural and non-natural tertiary-amide-based peptide oligomers indicates that these oligomers preferentially adopt a limited number of conformations.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Yuko
authors.identifier: 0000-0002-8104-283X
authors.initials: Y
authors.lastname: Otani
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.|National Center of Neurology and Psychiatry , 4-1-1 Ogawa-Higashimachi, Kodaira-shi, Tokyo 187-8551, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ohwada
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo , 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Kitao
mesh_terms: D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry*; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry*
chemical_list: D011743:Pyrimidines; D011392:Proline; D009584:Nitrogen; C072401:beta-proline