title: Comparison of intrinsic dynamics of cytochrome p450 proteins using normal mode analysis.
abstract: Cytochrome P450 enzymes are hemeproteins that catalyze the monooxygenation of a wide-range of structurally diverse substrates of endogenous and exogenous origin. These heme monooxygenases receive electrons from NADH/NADPH via electron transfer proteins. The cytochrome P450 enzymes, which constitute a diverse superfamily of more than 8,700 proteins, share a common tertiary fold but < 25% sequence identity. Based on their electron transfer protein partner, cytochrome P450 proteins are classified into six broad classes. Traditional methods of pro are based on the canonical paradigm that attributes proteins' function to their three-dimensional structure, which is determined by their primary structure that is the amino acid sequence. It is increasingly recognized that protein dynamics play an important role in molecular recognition and catalytic activity. As the mobility of a protein is an intrinsic property that is encrypted in its primary structure, we examined if different classes of cytochrome P450 enzymes display any unique patterns of intrinsic mobility. Normal mode analysis was performed to characterize the intrinsic dynamics of five classes of cytochrome P450 proteins. The present study revealed that cytochrome P450 enzymes share a strong dynamic similarity (root mean squared inner product > 55% and Bhattacharyya coefficient > 80%), despite the low sequence identity (< 25%) and sequence similarity (< 50%) across the cytochrome P450 superfamily. Noticeable differences in Cα atom fluctuations of structural elements responsible for substrate binding were noticed. These differences in residue fluctuations might be crucial for substrate selectivity in these enzymes.
authors.affiliation: Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, 54702.
authors.forename: Mariah E
authors.initials: ME
authors.lastname: Dorner
authors.affiliation: Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, 54702.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: McMunn
authors.affiliation: Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, 54702.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Bartholow
authors.affiliation: Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, 54702.
authors.forename: Brecken E
authors.initials: BE
authors.lastname: Calhoon
authors.affiliation: Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, 54702.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Conlon
authors.affiliation: Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, 54702.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Dulli
authors.affiliation: Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, 54702.
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Fehling
authors.affiliation: Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, 54702.
authors.forename: Cody R
authors.initials: CR
authors.lastname: Fisher
authors.affiliation: Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, 54702.
authors.forename: Shane W
authors.initials: SW
authors.lastname: Hodgson
authors.affiliation: Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, 54702.
authors.forename: Shawn W
authors.initials: SW
authors.lastname: Keenan
authors.affiliation: Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, 54702.
authors.forename: Alyssa N
authors.initials: AN
authors.lastname: Kruger
authors.affiliation: Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, 54702.
authors.forename: Justin W
authors.initials: JW
authors.lastname: Mabin
authors.affiliation: Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, 54702.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Mazula
authors.affiliation: Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, 54702.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Monte
authors.affiliation: Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, 54702.
authors.forename: Augustus
authors.initials: A
authors.lastname: Olthafer
authors.affiliation: Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, 54702.
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Sexton
authors.affiliation: Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, 54702.
authors.forename: Beatrice R
authors.initials: BR
authors.lastname: Soderholm
authors.affiliation: Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, 54702.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Strom
authors.affiliation: Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin, 54702.
authors.forename: Sanchita
authors.initials: S
authors.lastname: Hati
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D018360:Crystallography, X-Ray; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism*; D004579:Electron Transport; D006418:Heme / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013379:Substrate Specificity
chemical_list: D006418:Heme; D003577:Cytochrome P-450 Enzyme System
keywords: Cytochrome P450; P450 systems; normal mode analysis; protein dynamics; protein superfamily