title: Coupled motions during dynamics reveal a tunnel toward the active site regulated by the N-terminal α-helix in an acylaminoacyl peptidase.
abstract: Acylaminoacyl peptidase (AAP) subfamily belongs to the prolyl oligopeptidase (POP) family of serine-proteases. There is a great interest in the definition of molecular mechanisms related to the activity and substrate recognition of these complex multi-domain enzymes. The active site relies at the interface between the C-terminal catalytic domain and the β-propeller domain, whose N-terminal region acts as a bridge to the hydrolase domain. In AAP, the N-terminal extension is characterized by a structurally conserved α1-helix, which is known to affect thermal stability and thermal dependence of the catalytic activity. In the present contribution, results from hundreds nanosecond all-atom molecular dynamics simulations, along with analyses of the networks of cross-correlated motions of a member of the AAP subfamily are discussed. The MD investigation identifies a tunnel that from the surrounding of the N-terminal α1-helix bring to the catalytic site. This cavity seems to be regulated by conformational changes of the α1-helix itself during the dynamics. The evidence here provided can be a useful guide for a better understanding of the mechanistic aspects related to AAP activity, but also for drug design purposes.
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, P.zza della Scienza 2, 20126 Milan, Italy. elena.papaleo@unimib.it
authors.forename: Elena
authors.initials: E
authors.lastname: Papaleo
authors.forename: Giulia
authors.initials: G
authors.lastname: Renzetti
mesh_terms: D041522:Aeropyrum / Q000737:chemistry* / Q000201:enzymology; D019843:Archaeal Proteins / Q000737:chemistry*; D020134:Catalytic Domain; D030562:Databases, Protein; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D010447:Peptide Hydrolases / Q000737:chemistry*; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D055672:Static Electricity; D013696:Temperature; D013816:Thermodynamics
chemical_list: D019843:Archaeal Proteins; D010447:Peptide Hydrolases; C038220:acylaminoacyl-peptidase