Conformational behavior of flavin adenine dinucleotide

Conserved stereochemistry in bound and free states

Gopi Kuppuraj, Dennis Kruise, Kei Yura

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Metabolic enzymes utilize the cofactor flavin adenine dinucleotide (FAD) to catalyze essential biochemical reactions. Because these enzymes have been implicated in disease pathways, it will be necessary to target them via FAD-based structural analogues that can either activate/inhibit the enzymatic activity. To achieve this, it is important to explore the conformational space of FAD in the enzyme-bound and free states. Herein, we analyze X-ray crystallographic data of the enzyme-bound FAD conformations and sample conformations of the molecule in explicit water by molecular dynamics (MD) simulations. Enzyme-bound FAD conformations segregate into five distinct groups based on dihedral angle principal component analysis (PCA). A notable feature in the bound FADs is that the adenine base and isoalloxazine ring are oppositely oriented relative to the pyrophosphate axis characterized by near trans hypothetical dihedral angle "δV" values. Not surprisingly, MD simulations in water show final compact but not perfectly stacked ring structures in FAD. Simulation data did not reveal noticeable changes in overall conformational dynamics of the dinucleotide in reduced and oxidized forms and in the presence and/or absence of ions. During unfolding - folding dynamics, the riboflavin moiety is more flexible than the adenosine monophosphate group in the molecule. Conversely, the isoalloxazine ring is more stable than the variable adenine base. The pyrophosphate group depicts an unusually highly organized fluctuation illustrated by its dihedral angle distribution. Conformations sampled from enzymes and MD are quantified. The extent to which the protein shifts the distribution from the unbound state is discussed in terms of prevalent FAD shapes and dihedral angle population. (Graph Presented).

Original languageEnglish
Pages (from-to)13486-13497
Number of pages12
JournalJournal of Physical Chemistry B
Volume118
Issue number47
DOIs
Publication statusPublished - 2014 Nov 26
Externally publishedYes

Fingerprint

Stereochemistry
Flavin-Adenine Dinucleotide
adenines
stereochemistry
Enzymes
Dihedral angle
Conformations
enzymes
Molecular dynamics
Molecular Dynamics Simulation
dihedral angle
Adenine
molecular dynamics
Molecules
Computer simulation
Principal component analysis
riboflavin
adenosine monophosphate
Riboflavin
Water

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Materials Chemistry
  • Surfaces, Coatings and Films
  • Medicine(all)

Cite this

Conformational behavior of flavin adenine dinucleotide : Conserved stereochemistry in bound and free states. / Kuppuraj, Gopi; Kruise, Dennis; Yura, Kei.

In: Journal of Physical Chemistry B, Vol. 118, No. 47, 26.11.2014, p. 13486-13497.

Research output: Contribution to journalArticle

@article{e5929272acf64cdd8df309a868187bcd,
title = "Conformational behavior of flavin adenine dinucleotide: Conserved stereochemistry in bound and free states",
abstract = "Metabolic enzymes utilize the cofactor flavin adenine dinucleotide (FAD) to catalyze essential biochemical reactions. Because these enzymes have been implicated in disease pathways, it will be necessary to target them via FAD-based structural analogues that can either activate/inhibit the enzymatic activity. To achieve this, it is important to explore the conformational space of FAD in the enzyme-bound and free states. Herein, we analyze X-ray crystallographic data of the enzyme-bound FAD conformations and sample conformations of the molecule in explicit water by molecular dynamics (MD) simulations. Enzyme-bound FAD conformations segregate into five distinct groups based on dihedral angle principal component analysis (PCA). A notable feature in the bound FADs is that the adenine base and isoalloxazine ring are oppositely oriented relative to the pyrophosphate axis characterized by near trans hypothetical dihedral angle {"}δV{"} values. Not surprisingly, MD simulations in water show final compact but not perfectly stacked ring structures in FAD. Simulation data did not reveal noticeable changes in overall conformational dynamics of the dinucleotide in reduced and oxidized forms and in the presence and/or absence of ions. During unfolding - folding dynamics, the riboflavin moiety is more flexible than the adenosine monophosphate group in the molecule. Conversely, the isoalloxazine ring is more stable than the variable adenine base. The pyrophosphate group depicts an unusually highly organized fluctuation illustrated by its dihedral angle distribution. Conformations sampled from enzymes and MD are quantified. The extent to which the protein shifts the distribution from the unbound state is discussed in terms of prevalent FAD shapes and dihedral angle population. (Graph Presented).",
author = "Gopi Kuppuraj and Dennis Kruise and Kei Yura",
year = "2014",
month = "11",
day = "26",
doi = "10.1021/jp507629n",
language = "English",
volume = "118",
pages = "13486--13497",
journal = "Journal of Physical Chemistry B Materials",
issn = "1520-6106",
publisher = "American Chemical Society",
number = "47",

}

TY - JOUR

T1 - Conformational behavior of flavin adenine dinucleotide

T2 - Conserved stereochemistry in bound and free states

AU - Kuppuraj, Gopi

AU - Kruise, Dennis

AU - Yura, Kei

PY - 2014/11/26

Y1 - 2014/11/26

N2 - Metabolic enzymes utilize the cofactor flavin adenine dinucleotide (FAD) to catalyze essential biochemical reactions. Because these enzymes have been implicated in disease pathways, it will be necessary to target them via FAD-based structural analogues that can either activate/inhibit the enzymatic activity. To achieve this, it is important to explore the conformational space of FAD in the enzyme-bound and free states. Herein, we analyze X-ray crystallographic data of the enzyme-bound FAD conformations and sample conformations of the molecule in explicit water by molecular dynamics (MD) simulations. Enzyme-bound FAD conformations segregate into five distinct groups based on dihedral angle principal component analysis (PCA). A notable feature in the bound FADs is that the adenine base and isoalloxazine ring are oppositely oriented relative to the pyrophosphate axis characterized by near trans hypothetical dihedral angle "δV" values. Not surprisingly, MD simulations in water show final compact but not perfectly stacked ring structures in FAD. Simulation data did not reveal noticeable changes in overall conformational dynamics of the dinucleotide in reduced and oxidized forms and in the presence and/or absence of ions. During unfolding - folding dynamics, the riboflavin moiety is more flexible than the adenosine monophosphate group in the molecule. Conversely, the isoalloxazine ring is more stable than the variable adenine base. The pyrophosphate group depicts an unusually highly organized fluctuation illustrated by its dihedral angle distribution. Conformations sampled from enzymes and MD are quantified. The extent to which the protein shifts the distribution from the unbound state is discussed in terms of prevalent FAD shapes and dihedral angle population. (Graph Presented).

AB - Metabolic enzymes utilize the cofactor flavin adenine dinucleotide (FAD) to catalyze essential biochemical reactions. Because these enzymes have been implicated in disease pathways, it will be necessary to target them via FAD-based structural analogues that can either activate/inhibit the enzymatic activity. To achieve this, it is important to explore the conformational space of FAD in the enzyme-bound and free states. Herein, we analyze X-ray crystallographic data of the enzyme-bound FAD conformations and sample conformations of the molecule in explicit water by molecular dynamics (MD) simulations. Enzyme-bound FAD conformations segregate into five distinct groups based on dihedral angle principal component analysis (PCA). A notable feature in the bound FADs is that the adenine base and isoalloxazine ring are oppositely oriented relative to the pyrophosphate axis characterized by near trans hypothetical dihedral angle "δV" values. Not surprisingly, MD simulations in water show final compact but not perfectly stacked ring structures in FAD. Simulation data did not reveal noticeable changes in overall conformational dynamics of the dinucleotide in reduced and oxidized forms and in the presence and/or absence of ions. During unfolding - folding dynamics, the riboflavin moiety is more flexible than the adenosine monophosphate group in the molecule. Conversely, the isoalloxazine ring is more stable than the variable adenine base. The pyrophosphate group depicts an unusually highly organized fluctuation illustrated by its dihedral angle distribution. Conformations sampled from enzymes and MD are quantified. The extent to which the protein shifts the distribution from the unbound state is discussed in terms of prevalent FAD shapes and dihedral angle population. (Graph Presented).

UR - http://www.scopus.com/inward/record.url?scp=84913557557&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84913557557&partnerID=8YFLogxK

U2 - 10.1021/jp507629n

DO - 10.1021/jp507629n

M3 - Article

VL - 118

SP - 13486

EP - 13497

JO - Journal of Physical Chemistry B Materials

JF - Journal of Physical Chemistry B Materials

SN - 1520-6106

IS - 47

ER -