This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The adenovirus protease (AVP) is an enzyme essential for virus replication and hence is a target for antiviral drugs. The enzyme is activated upon the binding of a small peptide via a 53 amino acid signal transduction pathway. We have used simulated annealing based Nudged Elastic Band (NEB) techniques implemented within version 11 of the AMBER molecular dynamics code to predict low energy barrier activation pathways of AVP. Crystal structures obtained by the co-PI of both the inactivate and active forms of AVP provide the two end points of the activation pathway and the NEB code has been used to predict intermediates along this pathway. However, the NEB method necessarily places restrictions on the actual pathway. The simulation of unbiased activation pathways for AVP will provide critical information in the development of next generation antiviral drugs. We plan to run two 25 ?s unbiased MD trajectories. The first starting from the inactive enzyme structure immediately after activation with the pVIc peptide cofactor and the other starting from the active enzyme structure immediately after the removal of the activating pVIc peptide cofactor. These simulations will provide critical information regarding motions along the activation pathway that will provide specific target locations for AVP inhibition and also provide seed structures for more in-depth NEB investigations.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
3P41RR006009-20S1
Application #
8364351
Study Section
Special Emphasis Panel (ZRG1-BCMB-Q (40))
Project Start
2011-09-15
Project End
2013-07-31
Budget Start
2011-09-15
Budget End
2013-07-31
Support Year
20
Fiscal Year
2011
Total Cost
$1,094
Indirect Cost
Name
Carnegie-Mellon University
Department
Biostatistics & Other Math Sci
Type
Schools of Arts and Sciences
DUNS #
052184116
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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