ISSN:
1573-4951
Keywords:
Protein–ligand interactions
;
Molecular dynamics
;
AMBER 4.1
;
Allosteric communication
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract Neurophysins I and II (NPI and NPII) act in the neurosecretory granules as carrier proteinsfor the neurophyseal hormones oxytocin (OT) and vasopressin (VP), respectively. The NPI/OTfunctional unit, believed to be an (NPI/OT)2 heterotetramer, was modeled using low-resolution structure information, viz. the Cα carbon atom coordinates of the homologousNPII/dipeptide complex (file 1BN2 in the Brookhaven Protein Databank) as a template. Itsall-atom representation was obtained using standard modeling tools available within theINSIGHT/Biopolymer modules supplied by Biosym Technologies Inc. A conformation of theNPI-bound OT, similar to that recently proposed in a transfer NOE experiment, was dockedinto the ligand-binding site by a superposition of its Cys1-Tyr2 fragment onto the equivalentportion of the dipeptide in the template. The starting complex for the initial refinements wasprepared by two alternative strategies, termed Model I and Model II, each ending with a∼100 ps molecular dynamics (MD) simulation in water using the AMBER 4.1 force field. The freehomodimer NPI2 was obtained by removal of the two OT subunits from their sites, followedby a similar structure refinement. The use of Model I, consisting of a constrained simulatedannealing, resulted in a structure remarkably similar to both the NPII/dipeptide complex anda recently published solid-state structure of the NPII/OT complex. Thus, Model I isrecommended as the method of choice for the preparation of the starting all-atom data forMD. The MD simulations indicate that, both in the homodimer and in the heterotetramer, the310-helices demonstrate an increased mobility relative to the remaining body of the protein.Also, the C-terminal domains in the NPI2 homodimer are more mobile than the N-terminalones. Finally, a distinct intermonomer interaction is identified, concentrated around its mostprominent, although not unique, contribution provided by an H-bond from Ser25Oγ in one NPI unit to Glu81 Oε in the other unit. This interaction is present in the heterotetramer(NPI/OT)2 and absent or weak in the NPI2 homodimer. We speculate that this interaction,along with the increased mobility of the 310-helices and the carboxy domains, may contributeto the allosteric communication between ligand binding and NPI dimerization.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1008063025493
Permalink
