Protein flexibility predictions using graph theory

Donald J. Jacobs, A. J. Rader, Leslie A. Kuhn, Michael Thorpe

Research output: Contribution to journalArticle

536 Citations (Scopus)

Abstract

Techniques from graph theory are applied to analyze the bond networks in proteins and identify the flexible and rigid regions. The bond network consists of distance constraints defined by the covalent and hydrogen bonds and salt bridges in the protein, identified by geometric and energetic criteria. We use an algorithm that counts the degrees of freedom within this constraint network and that identifies all the rigid and flexible substructures in the protein, including overconstrained regions (with more crosslinking bonds than are needed to rigidify the region) and underconstrained or flexible regions, in which dihedral bond rotations can occur. The number of extra constraints or remaining degrees of bond-rotational freedom within a substructure quantifies its relative rigidity/flexibility and provides a flexibility index for each bond in the structure. This novel computational procedure, first used in the analysis of glassy materials, is approximately a million times faster than molecular dynamics simulations and captures the essential conformational flexibility of the protein main and side-chains from analysis of a single, static three-dimensional structure. This approach is demonstrated by comparison with experimental measures of flexibility for three proteins in which hinge and loop motion are essential for biological function: HIV protease, adenylate kinase, and dihydrofolate reductase.

Original languageEnglish (US)
Pages (from-to)150-165
Number of pages16
JournalProteins: Structure, Function and Genetics
Volume44
Issue number2
DOIs
StatePublished - Aug 1 2001
Externally publishedYes

Fingerprint

Graph theory
Proteins
HIV Protease
Adenylate Kinase
Tetrahydrofolate Dehydrogenase
Covalent bonds
Hinges
Molecular Dynamics Simulation
Rigidity
Crosslinking
Molecular dynamics
Hydrogen
Hydrogen bonds
Salts
Computer simulation

Keywords

  • Adenylate kinase
  • Conformational change
  • Coupled/collective motions
  • Dihedral angle constraints and rotations
  • Dihydrofolate reductase
  • Distance constraints
  • Hydrogen-bond networks
  • Mobility and dynamics
  • Structural stability

ASJC Scopus subject areas

  • Genetics
  • Structural Biology
  • Biochemistry

Cite this

Protein flexibility predictions using graph theory. / Jacobs, Donald J.; Rader, A. J.; Kuhn, Leslie A.; Thorpe, Michael.

In: Proteins: Structure, Function and Genetics, Vol. 44, No. 2, 01.08.2001, p. 150-165.

Research output: Contribution to journalArticle

Jacobs, DJ, Rader, AJ, Kuhn, LA & Thorpe, M 2001, 'Protein flexibility predictions using graph theory', Proteins: Structure, Function and Genetics, vol. 44, no. 2, pp. 150-165. https://doi.org/10.1002/prot.1081
Jacobs, Donald J. ; Rader, A. J. ; Kuhn, Leslie A. ; Thorpe, Michael. / Protein flexibility predictions using graph theory. In: Proteins: Structure, Function and Genetics. 2001 ; Vol. 44, No. 2. pp. 150-165.
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