Molecular dynamics of mouse acetylcholinesterase complexed with huperzine A

Two molecular dynamics simulations were performed for a modeled complex of mouse acetylcholinesterase liganded with huperzine A (HupA). Analysis of th ese simulations shows that HupA shifts in the active site toward Tyr 337 an d Phe 338 and that several residues in the active site area reach out to ma ke hydrogen bonds with the inhibitor. Rapid fluctuations of the gorge width are observed, ranging from widths that allow substrate access to the activ e site, to pinched structures that do not allow access of molecules as smal l as water. Additional openings or channels to the active site are found. O ne opening is formed in the side wall of the active site gorge by residues Val 73, Asp 74, Thr 83, Glu 84, and Asn 87 Another opening is formed at the base of the gorge by residues Trp 86, Val 132, Glu 202, Gly 448, and Ile 4 51. Both of these these openings have been observed separately in the Torpe do californica form of the enzyme. These channels could allow transport of waters and ions to and from the bulk solution. (C) 1999 John Wiley & Sons, Inc.