Docking studies on the complexed and uncomplexed FKBP12 structures with bound and unbound ligands: An implication of a conformational selection mechanism for binding

Yuan-Ping Pang, Norberto D. Silva, Christopher Haydock, Franklyn G. Prendergast

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Docking of FK506, rapamycin, and L-685,818 into their receptor, FKBP12, suggests that unlike the respective structures determined by X-ray crystallography, the uncomplexed FKBP12 structures determined by NMR may not be directly usable to identify high affinity ligands by docking studies for computational drug screening. In view of the resolution of the experimentally determined structures of FKBP12 and relatively small difference of the receptor binding sites between the complexed and uncomplexed states, it is unclear if the conformational induction mechanism is relevant to the binding of FKBP12 with its ligands. Alternatively, we advocate a conformation selection mechanism fundamentally akin to a mechanism proposed by Burgen. This mechanism better explains the experimental and calculated results for the binding of FKBP12 with FK506. It emphasizes that both guest and host select their most compatible preformed conformers to effect binding, and that the observed free energy of binding is a sum of the free energy change in complexation of the two most compatible conformers and the free energy changes in conversion of the Boltzmann-weighted principal conformers to the most compatible conformers. Conceptually, this mechanism represents one physical or nonphysical path of a thermodynamic cycle that is closed by the other path represented by the conformational induction mechanism, which can also be physical or nonphysical; it provides a theoretical means to estimate the affinity of the guest to the host with the experimentally available 3D structures of the two partners.

Original languageEnglish (US)
Pages (from-to)240-248
Number of pages9
JournalJournal of Molecular Modeling
Volume3
Issue number7
StatePublished - 1997

Fingerprint

Tacrolimus Binding Protein 1A
Free energy
Ligands
ligands
Tacrolimus
L 685818
X ray crystallography
free energy
Binding sites
Complexation
affinity
Conformations
induction
Screening
Preclinical Drug Evaluations
Nuclear magnetic resonance
Thermodynamics
thermodynamic cycles
X Ray Crystallography
Sirolimus

Keywords

  • Computational drug screening
  • Induced-fit
  • Key-lock
  • Recognition
  • SYSDOC

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Biophysics
  • Computer Science Applications
  • Computational Theory and Mathematics

Cite this

Docking studies on the complexed and uncomplexed FKBP12 structures with bound and unbound ligands : An implication of a conformational selection mechanism for binding. / Pang, Yuan-Ping; Silva, Norberto D.; Haydock, Christopher; Prendergast, Franklyn G.

In: Journal of Molecular Modeling, Vol. 3, No. 7, 1997, p. 240-248.

Research output: Contribution to journalArticle

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