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Simulation of the activation of -chymotrypsin: Analysis of the pathway and role of the propeptide

Laboratory of Biomolecular Dynamics, Katholieke Universiteit Leuven, B-3001 Leuven, Belgium

(RECEIVED April 21, 2004; FINAL REVISION August 6, 2004; ACCEPTED August 14, 2004)

-Chymotrypsin undergoes a reversible conformational change from an inactive chymotrypsinogen-like structure at high pH to an active conformation at neutral pH. In order to gain insight into this process on a structural level, we applied molecular dynamics and targeted molecular dynamics simulations in aqueous environment on the activation and inactivation processes of three different types of chymotrypsin. These are the wild-type bovine chymotrypsin containing the propeptide and the bovine and rat chymotrypsin lacking the propeptide. From these simulations, the importance of the propeptide and of the sequence differences between the rat and bovine variants from the viewpoint of activation could be evaluated and compared with previous fluorescence stopped flow results. The obtained results show the unambiguous influence of the propeptide on the explored conformational space, whereas the sequence differences between bovine and rat chymotrypsin play a minor role. The main features of activation are present in both the wild type and the variant lacking the propeptide, despite the fact that different parts of the conformational space were explored. The comparison of all trajectories shows that particular amino acid residues, such as 17, 18, 19, 187, 217, 218, and 223, undergo large dihedral transitions during the activation process, suggesting a role as hinge residues during the conformational change.

Keywords: conformational change; molecular dynamics simulation; targeted molecular dynamics; pathway calculation; chymotrypsinogen; chymotrypsin; A-chain (propeptide); fluorescence stopped flow

Abbreviations: rms, root mean square • MD, molecular dynamics • rmsd, root mean square deviation • TMD, targeted molecular dynamics • A-chymotrypsin, variants without propeptide (A-chain) • WT, wild-type variants with pro-peptide (A-chain) • letter "b," bovine variants • letter "r," rat variants • ac, active form • in, inactive form • bWTac, active conformation of bovine wild-type chymotrypsin • bWTin, inactive conformation of bovine wild-type chymotrypsin • bAac, active conformation of bovine chymotrypsin without propeptide • bAin, inactive conformation of bovine chymotrypsin without propeptide • rAac, active conformation of rat chymotrypsin without propeptide • rAin, inactive conformation of rat chymotrypsin without propeptide

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.04825004.

Reprint requests to: Yves Engelborghs, Katholieke Universiteit Leuven, Laboratory of Biomolecular Dynamics, Celestijnenlaan 200D, B-3001 Leuven, Belgium; e-mail: Yves.Engelborghs{at}fys.kuleuven.ac.be; fax: +3216327982.

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