From the Hydrophobic Core to the Globular-Disorder Interface: New Challenges and Insights into Protein Design

Despite recent success brought in the field of protein folding and design by deep learning and Alpha-Fold, the biophysical basis of protein folding still remain largely unexplained. A growing interest in the community revolves around moving towards ‘Interpretable Machine Learning (ML) & Artificial Intelligence (AI)’ methods to better explain underlying events of the protein folding process, possibly maintaining an already accomplished high accuracy of sequence to structure predictions. However, these fields, are in the early days of development.

During the last few decades, a much more viable approach has focused on addressing the ‘inverse protein folding problem’, a rising approach in protein de novo design.

In recent years, the field has undoubtedly become diverse and complex. New endeavors such as peptide design (targeted to design bio-therapeutics), plausible design of fold-switch proteins, and proteins with targeted functional modulations all are now part of protein design. The most intriguing and challenging of these problems is perhaps the design and design attempts that handle ‘disorder and disorder-to-order transitions’ in proteins, ever since the discovery of intrinsically disordered proteins (IDPs).

A primary challenge of contemporary protein design would be to address the ever-so-subtle ‘globular-disorder’ evolutionary interface in proteins. A successful endeavor along this direction would be of high biophysical and mechanistic importance. Furthermore, findings in this area would also serve great therapeutic benefits in the wide array of IDP-related deadly human diseases. Though there is not yet a general evolutionary rule regarding the origin of disordered and globular proteins, instances of successful design (for example) of folded globular repeats from disordered ancestors has raised much hope. The field is currently being enriched with a diverse plethora of innovative ideas and insights to explore new design strategies. On one end, alternative modes of side-chain packing have lately been revealed compatible to a given protein fold (or a hydrophobic core) in globular proteins. At the other end, cumulative point mutations have been shown to be the key mechanism in triggering disorder-to-globular transitions. The characteristic binding promiscuity of IDPs (attributed to their physical flexibility) has also been explained to be sustained by transient (avalanche type) phase transition dynamics involving salt-bridges. Together, these findings offer an exciting ‘protein design’ platform to explore the yet unraveled ‘disorder code in proteins’. One of the long-term goals is to develop a scanning mutation library that can serve as a non-discrete regulatory switch between related lineages of globular and disordered proteins.

This Research Topic welcomes Original Research Articles / Brief Reports / Reviews / Commentaries on experimental and/or theoretical computational advances in protein design themed on any of the following:

• New strategies and methods in protein design addressing protein disorder and disorder-to-order transitions in proteins
• Design of alternatively packed hydrophobic cores: new insights and perspectives
• Design/design attempts of folded globules from their disordered ancestors
• Exploring the mutational space between related lineages of disordered and globular proteins
• Biophysical insights into the origin of protein disorder – probed by protein design


We would like to acknowledge Dr. Abhirup Bandyopadhyay, of Aix-Marseille Université who has acted as coordinator and has contributed to the preparation of the proposal for this Research Topic.

We would also like to acknowledge Dr. Nalok Dutta, of Washington State University who has acted as coordinator and has contributed to the preparation of the proposal for this Research Topic.