title: The Effect of Newly Developed OPLS-AA Alanyl Radical Parameters on Peptide Secondary Structure.
abstract: Recent studies using ab initio calculations have shown that Cα-centered radical formation by H-abstraction from the backbone of peptide residues has dramatic effects on peptide structure and have suggested that this reaction may contribute to the protein misfolding observed in Alzheimer's and Parkinson's diseases. To enable the effects of Cα-centered radicals to be studied in longer peptides and proteins over longer time intervals, force-field parameters for the Cα-centered Ala radical were developed for use with the OPLS force field by minimizing the sum of squares deviation between the quantum chemical and OPLS-AA energy hypersurfaces. These parameters were used to determine the effect of the Cα-centered Ala radical on the structure of a hepta-alanyl peptide in molecular dynamics (MD) simulations. A negligible sum-of-squares energy deviation was observed in the stretching parameters, and the newly developed OPLS-AA torsional parameters showed a good agreement with the LMP2/cc-pVTZ(-f) hypersurface. The parametrization also demonstrated that derived force-field bond length and bond angle parameters can deviate from the quantum chemical equilibrium values, and that the improper torsional parameters should be developed explicitly with respect to the coupled torsional parameters. The MD simulations showed planar conformations of the Cα-containing residue (Alr) are preferred and these conformations increase the formation of γ-, α-, and π-turn structures depending on the position in the turn occupied by the Alr residue. Higher-ordered structures are destabilized by Alr except when this residue occupies position "i + 1" of the 310-helix. These results offer new insight into the protein-misfolding mechanisms initiated by H-abstraction from the Cα of peptide and protein residues.
authors.affiliation: Materials Science Research Institute, Faculty of Dentistry, Semmelweis University , Üllöi út 26. H-1085 Budapest, Hungary.|Department of Chemical Informatics, Faculty of Education, University of Szeged , Boldogasszony sgt. 6, H-6725 Szeged, Hungary.|Global Institute of Computational Molecular and Materials Science ( www.giocomms.org ).|Drug Discovery Research Center ( www.drugcent.com ).
authors.forename: Michael C
authors.initials: MC
authors.lastname: Owen
authors.affiliation: Thrombosis and Haemostasis Research Group of the Hungarian Academy of Sciences at the University of Debrecen , H-4010, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Tóth
authors.affiliation: Department of Chemical Informatics, Faculty of Education, University of Szeged , Boldogasszony sgt. 6, H-6725 Szeged, Hungary.|Drug Discovery Research Center ( www.drugcent.com ).
authors.forename: Balázs
authors.initials: B
authors.lastname: Jojárt
authors.affiliation: Thrombosis and Haemostasis Research Group of the Hungarian Academy of Sciences at the University of Debrecen , H-4010, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Komáromi
authors.affiliation: Materials Science Research Institute, Faculty of Dentistry, Semmelweis University , Üllöi út 26. H-1085 Budapest, Hungary.|Department of Chemistry, University of Toronto , Toronto, Ontario M5S 3H6, Canada.|Department of Chemical Informatics, Faculty of Education, University of Szeged , Boldogasszony sgt. 6, H-6725 Szeged, Hungary.|Global Institute of Computational Molecular and Materials Science ( www.giocomms.org ).|Drug Discovery Research Center ( www.drugcent.com ).
authors.forename: Imre G
authors.initials: IG
authors.lastname: Csizmadia
authors.affiliation: Department of Chemical Informatics, Faculty of Education, University of Szeged , Boldogasszony sgt. 6, H-6725 Szeged, Hungary.|Drug Discovery Research Center ( www.drugcent.com ).
authors.forename: Bela
authors.initials: B
authors.lastname: Viskolcz