Molecular Dynamics of Acetylcholinesterase Dimer Complexed with Tacrine

Włodek, S.; Clark, Terry; Scott, and L. Ridgway; McCammon, J. Andrew

doi:10.1021/ja971226d

Cited by 163 publications

(168 citation statements)

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“…This difference could cause a difference in hydrogen bonding, electrostatic, and van der Waals interactions during the catalytic process, and result in a significant difference in free energies of activation. Nevertheless, the basic BChE mechanism for both enantiomers may resemble the common catalytic mechanism for ester hydrolysis in other serine hydrolases [32,39], including the thoroughly investigated AChE [40,41,42,43,44].…”

Section: Fundamental Reaction Pathway For Bche-catalyzed Hydrolysis Omentioning

confidence: 99%

Rational design of an enzyme mutant for anti-cocaine therapeutics

Zheng

Chen

2007

J Comput Aided Mol Des

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Summary(−)-Cocaine is a widely abused drug and there is no available anti-cocaine therapeutic. The disastrous medical and social consequences of cocaine addiction have made the development of an effective pharmacological treatment a high priority. An ideal anti-cocaine medication would be to accelerate (−)-cocaine metabolism producing biologically inactive metabolites. The main metabolic pathway of cocaine in body is the hydrolysis at its benzoyl ester group. Reviewed in this article is the stateof-the-art computational design of high-activity mutants of human butyrylcholinesterase (BChE) against (−)-cocaine. The computational design of BChE mutants has been based on not only the structure of the enzyme, but also the detailed catalytic mechanisms for BChE-catalyzed hydrolysis of (−)-cocaine and (+)-cocaine. Computational studies of the detailed catalytic mechanisms and the structure-and-mechanism-based computational design have been carried out through the combined use of a variety of state-of-the-art techniques of molecular modeling. By using the computational insights into the catalytic mechanisms, a recently developed unique computational design strategy based on the simulation of the rate-determining transition state has been employed to design highactivity mutants of human BChE for hydrolysis of (−)-cocaine, leading to the exciting discovery of BChE mutants with a considerably improved catalytic efficiency against (−)-cocaine. One of the discovered BChE mutants (i.e. A199S/S287G/A328W/Y332G) has a ~456-fold improved catalytic efficiency against (−)-cocaine. The encouraging outcome of the computational design and discovery effort demonstrates that the unique computational design approach based on the transition-state simulation is promising for rational enzyme redesign and drug discovery.

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Section: Fundamental Reaction Pathway For Bche-catalyzed Hydrolysis Omentioning

confidence: 99%

Rational design of an enzyme mutant for anti-cocaine therapeutics

Zheng

Chen

2007

J Comput Aided Mol Des

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“…It has always been hard to simulate molecular dynamics on time scales that are biologically significant. Although it has been demonstrated that parallelism (using a spatial decomposition) can allow very large problems to be solved efficiently [12], the efficient use of parallelism to extend the time of simulation for a fixed-size problem has been elusive. Decomposition of the time domain provides one possible option [2,10].…”

Section: A Long-standing Challengementioning

confidence: 99%

Education and Research Challenges in Parallel Computing

Scott

Clark

Bagheri

2005

Lecture Notes in Computer Science

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Abstract. Over three decades of parallel computing, new computational requirements and systems have steadily evolved, yet parallel software remains notably more difficult relative to its sequential counterpart, especially for fine-grained parallel applications. We discuss the role of education to address challenges posed by applications such as informatics, scientific modeling, enterprise processing, and numerical computation. We outline new curricula both in computational science and in computer science. There appear to be new directions in which graduate education in parallel computing could be directed toward fulfilling needs in science and industry.

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“…the diisopropylphosphofluoridate hydrolase (DFPase) of the squid head ganglion (64), are homologous members of a small number of families displaying substantial structural similarity. In the case of the phosphotriesterase from Pseudomonas, which is known to hydrolyze both paraoxon and parathion (65), it has been clearly established that it shows no homology with human paraoxonase, which does not hydrolyze parathion (66). The molecular structure of the phosphotriesterase was recently solved to 2.1 Ä resolution (67,68).…”

Section: Work On Tcache Involves Two Principal Topicsmentioning

confidence: 99%

“…Molecular dynamics (MD) simulations have suggested that an alternative route of access to the active site might open via the concerted movement of residues W84, VI29, and G441 , while a more recent MD study has identified a number of "side entrances" to the gorge, all involving concerted movements of a number of side chains in the Q loop (C67-C92) of AChE (Wlodek et al, 1997b). As yet, no simple and predictive model for the clearance of the products of hydrolysis of ACh or BCh has been introduced into the treatment of the molecular traffic of substrates and ligands through the active site of ChEs.…”

Section: Introductionmentioning

confidence: 99%

X-Ray Crystallographic Studies on Acetylcholinesterase and Related Enzymes

Sussman¹,

Silman²

2003

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REPORT DOCUMENTATION PAGEForm ifl burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining ed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for lul&Vn to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and TITLE AND SUBTITLE X-Ray Crystallographic Studies on Acetylcholinesterase and Related Enzymes AUTHOR(S)Joel L. Sussman, Ph.D. I. Silman, Ph.D. FUNDING NUMBERS DAMD17-97-2-7022 PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)Weizmann Institute of Science Rehovot 76100 Israel E-MAIL: j oel.sussman@weizmann. ac.il Where copyrighted material is quoted, permission has been obtained to use such material. PERFORMING ORGANIZATION REPORT NUMBER SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES)UWhere material from documents designated for limited distribution is quoted, permission has been obtained to use the material.Citations of commercial organizations and trade names in this report do not constitute an official Department of Army endorsement or approval of the products or services of these organizations.N/A In conducting research using animals, the investigator(s) adhered to the "Guide for the Care and Use of Laboratory Animals," prepared by the Committee on Care and use of Laboratory Animals of the Institute of Laboratory Resources, national Research Council (NIH Publication No. 86-23, Revised 1985). N/A For the protection of human subjects, the investigator(s) adhered to policies of applicable Federal Law 45 CFR 46. N/A In conducting research utilizing recombinant DNA technology, the investigator(s) adhered to current guidelines promulgated by the National Institutes of Health. N/A Zh the conduct of research utilizing recombinant DNA, the investigator(s) adhered to the NIH Guidelines for Research Involving Recombinant DNA Molecules. N/A In the conduct of research involving hazardous organisms, the investigator(s) adhered to the CDC-NIH Guide for Biosafety in Microbiological and Biomedieal Laboratories.l->r*iA. J J*-»

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Molecular Dynamics of Acetylcholinesterase Dimer Complexed with Tacrine

Cited by 163 publications

References 44 publications

Rational design of an enzyme mutant for anti-cocaine therapeutics

Rational design of an enzyme mutant for anti-cocaine therapeutics

Education and Research Challenges in Parallel Computing

X-Ray Crystallographic Studies on Acetylcholinesterase and Related Enzymes

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