Computational investigations on the dynamic binding effect of molecular tweezer CLR01 toward intrinsically disordered HIV‐1 Nef

Abstract

Intrinsically disordered proteins (IDPs) are highly flexible molecules that undergo disorder to order transition through their interaction with other molecules. IDPs play a vital role in several biological processes ranging from molecular recognition to several human diseases through the protein-protein interaction. The dynamic flexibility of IDPs and their implications in several human diseases enable these molecules to serve as novel therapeutic targets. However, the challenging task is to develop novel drugs against IDPs because of their lack of stable structures and the nature of high conformational flexibility. In this study, we have calculated the dynamic binding effect of the supramolecular tweezer CLR01 against the intrinsically disordered HIV-1 Nef by employing molecular docking and dynamics simulation approaches. From docking results, we predicted the strong binding affinity of the tweezer with the target residues of Nef. The docking results were further validated from the molecular dynamics simulation studies confirming the conformational stability of Nef upon tweezer binding. These findings provide useful insights into the development of potent inhibitors for targeting Nef protein functions.

Atomic Details of Carbon-Based Nanomolecules Interacting with Proteins

“…Intrinsic disorder is a key feature of partners that bind 14-3-3 proteins and, therefore, tweezer can provide useful insight in how to stabilize these interactions [128,129]. In summary, CLR01 can be used to tune protein-protein interactions by affecting the binding affinity of specific proteins/peptides, or the changing the dynamic flexibility of intrinsically disordered proteins [125,130]. A rigid C-shaped skeleton combined with a negatively charged phosphate group is well suited to interact and explore long positive charges of surface Arg or Lys residues.…”