Albany 2019: 20th Conversation - Abstracts

category image Albany 2019
Conversation 20
June 11-15 2019
Adenine Press (2019)

Computational Modeling and Engineering of Allosteric Regulatory Mechanisms in Signaling Proteins: Integration of Multiscale Simulations, Network Biology and Machine Learning

A systems-based drug discovery approach is introduced that incorporates chemical biology and network modeling for designing allosteric modulators of protein kinases and molecular chaperones. The allosteric interactions allow for molecular communication and event coupling in signal transduction pathways and networks. The overarching goal of understanding molecular principles underlying recognition of protein kinase clients and chaperone-based modulation of kinase activity is fundamental to activity of many signaling proteins. The synergistic roles of the Hsp90-Cdc37 chaperone machinery and protein kinases in biology and disease have stimulated extensive structural and functional studies of regulatory mechanisms. Allosteric interactions of the Hsp90 with cochaperones and protein kinase clients (left panel of the figure) derived from recent crystal structures (Verba & Agard, 2017) can determine regulatory mechanisms and cellular functions of many signaling proteins and cascades. We report the results of multiscale simulations and network biology studies of the Hsp90 chaperones and a panel of protein kinases with an atomic level analysis of regulatory dynamic changes and binding of these protein systems in signaling networks (Czemeres, Buse & Verkhivker, 2017). The results of biophysical and computational biology studies combined with biochemical experiments have been used to derive a network model of kinase regulation by Hsp90 chaperones (shown on the right panel of the figure). Among our primary findings is the evidence that a small number of functional motifs may be utilized by the chaperone and protein kinases to act as central regulators of protein client binding in signaling networks. This work has offered atomistic insights into mechanisms of kinase activation by molecular chaperones orchestrated by direction-specific cross-talk between key regulatory regions. The developed platform of atomistic simulations and network biology approaches is also integrated with machine learning-based models of allosteric regulation for oncogenic proteins in signaling cascades.

verkhi-fig.gif This research has been supported by institutional funding from Chapman University.


    Verba, K.A. &Agard, D.A. (2017) How Hsp90 and Cdc37 lubricate kinase molecular switches. Trends Biochem Sci., 42, 799-811.

    Czemeres J., Buse, K. & Verkhivker GM. (2017) Atomistic simulations and network-based modeling of the Hsp90-Cdc37 chaperone binding with Cdk4 client protein: A mechanism of chaperoning kinase clients by exploiting weak spots of intrinsically dynamic kinase domains. PLoS One. 12(12):e0190267.

Gennady M.Verkhivker a,b*
Steve Agajanian a,
Nathaniel Bischoff a,
Lindy Astl a
Kristin Blacklock a,c

a,Department of Biomedical and Pharmaceutical Sciences
Schmid College of Science & Technology and School of Pharmacy
Chapman University
Irvine CA 92866,USA

,b Department of Pharmacology
University of California San Diego
San Diego CA 92093, USA

cDepartment of Chemistry and Chemical Biology
Rutgers University
Piscataway NJ, 08854, USA

Phone: (714) 516-4586
Fax: (714) 532-6048
Email: verkhivk@chapman.edu