Liu, Shuhan
(2020)
In Silico Simulation of DUSP-YIV906 Protein-Ligand Interactions and DUSP3-ERK Protein-Peptide Interactions.
Master's Thesis, University of Pittsburgh.
(Unpublished)
Abstract
The dual-specificity phosphatases (DUSPs) are a heterogeneous group of protein enzymes that modulate several critical cellular signaling pathways by dephosphorylating the phosphotyrosine and phosphoserine/phosphothreonine residues within their substrate proteins. One of the best characterized sub-group of DUSPs is the mitogen-activated protein kinase phosphatases (MKPs), which act as the antagonists of associated signaling cascades including the extracellular signal-regulated kinases (ERKs) pathways. Accumulated evidences have highlighted the therapeutic value of DUSPs, as deletion or inhibition of some DUSPs can increase the phosphorylated level of ERKs to cause cancer cell death. In this study, multi-scale molecular modeling simulations were first performed to investigate the mechanism of action of YIV-906, which is an herbal formulation used in cancer treatment targeting DUSP-ERK1/2 pathways. In total, MD simulations and binding free energy calculations were performed for 99 DUSP-ligand complexes. Our results demonstrate that the sulfate moieties and carboxyl moieties of the advantageous ligands, either original herbal chemicals or human metabolites from YIV-906, can occupy the enzymes’ catalytic sites, mimicking the endogenous phosphate substrates of DUSPs. With the second aim to improve the accuracy of protein-peptide docking between DUSP3 and a peptide fragment of ERK1/2, a new receptor residue mapping (RR mapping) algorithm was developed to identify hotspots residues on the surface of DUSP3 and improve the peptide docking scoring. By performing all-atom molecular dynamics (MD) simulations with the receptor being soaked in a water box containing 0.5 moles of capped dipeptide of 20 natural amino acids (AA) plus 3 phosphorylated non-standard AAs, the RR maps with probabilities of AAs interacting with DUSP3’s surface residues were obtained. With the interaction probabilities incorporated, the ERK peptide binding models yielded by protein-peptide docking can be re-ranked and generate more accurate predictions. We have demonstrated that multi-scale molecular modeling techniques are able to elucidate molecular mechanisms involving complex molecular systems. Finally, our modeling study provides useful insights into the rational design of high potent anti-cancer drugs targeting DUSPs, and the new RR mapping algorithm is a promising tool that can be universally applied in characterization of protein-protein interactions (PPIs).
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
20 April 2020 |
| Date Type: |
Publication |
| Defense Date: |
19 March 2020 |
| Approval Date: |
20 April 2020 |
| Submission Date: |
7 April 2020 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
13 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
MS - Master of Science |
| Thesis Type: |
Master's Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
DUSP, ERK, YIV-906, docking, MD, PPI |
| Related URLs: |
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| Date Deposited: |
20 Apr 2020 13:55 |
| Last Modified: |
20 Apr 2020 13:55 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/38610 |
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