Artificial proteins modulate allostery of PDZ3 and SH3 in two domains constructs. A computational characterization of novel chimeric proteins

Palani Kirubakaran, Lucie Pfeiferová, Jiří Vondrášek*

Institute of Organic Chemistry and Biochemistry, Flemingovo náměstí 2, Prague 6, 160 10, Czech Republic.

Artificial multi-domain proteins with increased structural and functional properties can be utilized in a broad spectrum of applications. The design of chimeric fusion proteins utilizing protein domains or one-domain miniproteins as building blocks is an important advancement for the creation of new biomolecules for biotechnology and medical applications. However, we critically miss computational studies to describe in details dynamics and geometry properties of two domain constructs made from structurally and functionally different proteins. In this article we attempt to test our in silico design strategy using all-atom explicit solvent molecular dynamics simulations. The well characterized PDZ3 and SH3 domains of human zonula occludens (ZO-1) (3TSZ) along with other 5 artificial domains and two kind of molecular linkers were selected to construct chimeric two domains molecules. The influence of the artificial domains on the structure and dynamics of the  PDZ3 and SH3 were determined using a range of analysis. This approach allowed us to describe the artificial domains as allostery modulators of the PDZ3 and SH3 domains.