Abstract
Entangled with inherent sensitivity to its environment; proteins, nature’s workhorse performs extraordinary tasks vital for the upkeep of the biological world. Conjugating proteins with polymers has been used as a strategy to exploit these functional capabilities beyond their natural limits. However, the molecular level effects of using initiator compounds are not well understood and left unexploited. In this work, we demonstrate that initiator cluster formation reduces the charge–charge repulsions between Lys side chains, on a model protein, and brings them closer to each other through increased non-polar interactions. Crucially, it is found that initiator clusters imposed more conformational stability to a previously identified highly dynamic unstructured C-terminal region of the model protein, without altering the protein’s global structure-dynamic relationship. The possibility of computationally identified initiator cluster formation has enormous potential to allow experimental techniques, such as X-ray crystallographic, to resolve highly dynamic, unstructured regions of a protein, i.e. intrinsically disordered regions, without altering the protein’s global structure-dynamic relationship and thus its stability and activity. This can prove to be a game changer of the field.
GRAPHICAL ABSTRACT
Acknowledgments
We dedicate this work to Prof. Michael Klein. His contributions to computational chemistry, intermolecular interactions, and the modelling of biophysical systems for over five decades have influenced dramatically not only these fields, but the lives of so many researchers.
The authors acknowledge the financial support provided by the University of Florida Preeminence Initiative, the Graduate School Fellowship of University of Florida, and the computational support provided by the University of Florida Research Computing.
Disclosure statement
No potential conflict of interest was reported by the authors.