Novel structural element bridges de novo protein design challenge of functional protein-ligand interactions

Essay from the year 2021 in the subject Biology - Micro- and Molecular Biology, grade: 1,0, University of Heidelberg, course: Ausgewahlte Themen der Molekularen Biotechnologie (unter Einbeziehung von Vortragstechniken und wissenschaftlichem Englisch), language: English, abstract: De novo protein design aims to create novel protein folds from scratch without sequence homologies to any known proteins. These proteins introduce new ligand-protein interactions. Targeting small, polar ligands with structural complexity has remained a great challenge for protein engineers. Methods applied involved ligand-appended rotamers that often failed due to the lever-arm effect - Minor uncertainties in the location of ligand and protein backbone snowballed. A van der Mer (vdM) is a structural unit consisting of an amino acid and an interacting chemical group. Therefore, both of their coordinates unite. The element allows for a precise design which is directed towards functional groups of the ligand. The Convergent Motifs for Binding Sites algorithm selects vdMs with favorable interactions. The Rosetta program is used for flexible backbone design and ab initio folding predictions. Six proteins were designed by this protocol that bind apixaban. Two proteins bound the drug effectively. Potentially, the method can be applied to design more ligand-binding proteins and protein-protein interactions. For instance, these findings could drive the development nanomaterials based on proteins forward. Consequently, vdMs provide an innovative approach to de novo protein design.