A computational study of radical initiated protein backbone homolytic dissociation on all natural amino acids.
Hydroxyl radical (˙OH) is known to be one of the most reactive species. In this work, the hydrogen abstraction by ˙OH from Cαand Cβatoms of all amino acids is studied in the framework of density functional theory as this is the most favorable reaction mechanism when this kind of radical attacks a protein. From the myriad routes that the oxidation of a protein by a ˙OH radical may follow, fragmentation of the protein is one of the most damaging ones as it hampers the normal function of the protein. Therefore, cleavages of the Cα-C and Cα-N backbone bonds have been investigated as the second step of the mechanism. To the best of our knowledge, this is the first time that this reaction pathway has been systematically studied for all natural amino acids. The study includes the effects that the solvent dielectrics or the conformation of the peptide model employed has on the reaction. Interestingly, the results indicate that the nature of the side chain has little effect on the H abstraction reaction, and that for most of amino acids the attack at the Cαatom is favored over the attack at the Cβatom. The origin of this preference relies on the larger capability of the formed radical intermediate to delocalize the unpaired electron, thus maximizing the captodative effect. Moreover, the reaction is more favorable when the reactant presents a β-sheet conformation, with a completely planar peptide backbone. With respect to the homolytic splitting of the Cα-C and Cα-N bonds, the former is favorable for almost all amino acids, whereas Ser and Thr are the only amino acids favoring the latter. These results agree with previous investigations but an accurate description of the electronic density analysis performed indicates that the origin of the different reaction pathway preferences relies on a large stabilization of the product rather than bond weakening at the radical intermediate.
Kimika Fakultatea, Euskal Herriko Unibertsitatea (UPV/EHU) and Donostia International Physics Center (DIPC), PK 1072, 20080 Donostia, Euskal Herria, Spain. joni.mujika@ehu.eus.
Jon
J
Uranga
Institut Catala d'Investigacio Quimica (ICIQ), Av. Paissos Catalans, 16, 43007 Tarragona, Catalunya, Spain.
Oier
O
Lakuntza
Kimika Fakultatea, Euskal Herriko Unibertsitatea (UPV/EHU) and Donostia International Physics Center (DIPC), PK 1072, 20080 Donostia, Euskal Herria, Spain. joni.mujika@ehu.eus and Department of Chemistry, University of California Berkeley, 94720 Berkeley, CA, USA.
Eloy
http://orcid.org/0000-0002-6558-7821
E
Ramos-Cordoba
Kimika Fakultatea, Euskal Herriko Unibertsitatea (UPV/EHU) and Donostia International Physics Center (DIPC), PK 1072, 20080 Donostia, Euskal Herria, Spain. joni.mujika@ehu.eus.
Jon M
JM
Matxain
Kimika Fakultatea, Euskal Herriko Unibertsitatea (UPV/EHU) and Donostia International Physics Center (DIPC), PK 1072, 20080 Donostia, Euskal Herria, Spain. joni.mujika@ehu.eus.
Jon I
http://orcid.org/0000-0002-4584-7497
JI
Mujika
D000596:Amino Acids / Q000737:chemistry*; D004583:Electrons; D006859:Hydrogen; D017665:Hydroxyl Radical; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D010455:Peptides / Q000737:chemistry; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*
D000596:Amino Acids; D010455:Peptides; D011506:Proteins; D017665:Hydroxyl Radical; D006859:Hydrogen