A mutant of human butyrylcholinesterase (BChE) with high activity against cocaine would be highly promising as a drug for therapeutic treatment of cocaine abuse and overdose. It is desirable to design a recombinant BChE mutant with a long half-life in human circulation. Studies showed that BChE subunits can be assembled by a peptide containing the proline-rich attachment domain (PRAD) to form a stable tetramer. The models of BChE tetramer complexed with PRAD with various sequences have been constructed, in the present study, on the basis of homology modeling and molecular dynamics simulation of explicit water-solvated systems. The 3D models enable us to understand how the BChE subunits are arranged in the tetramer and how the tetramerization domain of BChE is associated with PRAD to form a stable tetramer of human BChE. It has been shown that the six conserved hydrophobic residues located on the C-terminal of BChE are responsible for the key electrostatic and hydrophobic interactions between the tetramerization domain of BChE and PRAD. The simulated tetramer structures suggest that mutation of three residues, i.e., Phe547, Met554, and Phe561, to other hydrophobic residues may be beneficial for increasing the binding between the tetramerization domain of BChE and PRAD. Thus, the detailed structural insights obtained from this study may be valuable for rational design of a recombinant BChE tetramer with a longer residence time in circulation.
|Number of pages||10|
|Journal||Journal of Physical Chemistry B|
|State||Published - May 7 2009|
ASJC Scopus subject areas
- Physical and Theoretical Chemistry
- Surfaces, Coatings and Films
- Materials Chemistry