Finding order within intrinsically disordered proteins

The structure of a protein determined by its amino acid sequence is a cornerstone of molecular biology. The idea, known as Anfinsen’s dogma, is generally true, although some classes of proteins are thought to present an exception to the rule.

Intrinsically disordered proteins (IDPs) pose one exception, as they have no single fixed structure. Instead, their structure changes based on their environment and neighboring proteins.

Kulkarni et al. review the nature of the IDPs and how they probe the limits of Anfinsen’s dogma. Recent conceptual and technological advances in energy landscape visualization, parallel tempering, and molecular dynamics simulations to study IDPs are discussed.

“The review highlights the difficulties in studying IDPs and discusses the latest developments in discerning the conformational preferences of the IDPs,” said author Prakash Kulkarni.

Those conformational preferences emanating from IDP dynamics are distinct from the transcriptional noise and are thought to act in concert to relay and amplify such noise.

The researchers argue IDPs exist as ensembles that are highly dynamic and exhibit conformational preferences. IDPs are not random coils and do have structure, no matter how subtle. Discerning the structure can shed new light on how IDPs impact cellular decision making.

They highlight the significance of IDPs as therapeutic targets, which until recently were considered to be undruggable, and discuss recent advances in rational drug discovery targeting IDPs.

Source: “Intrinsically disordered proteins: Ensembles at the limits of Anfinsen’s dogma,” by Prakash Kulkarni, Vitor B. P. Leite, Susmita Roy, Supriyo Bhattacharyya, Atish Mohanty, Srisairam Achuthan, Divyoj Singh, Rajeswari Appadurai, Govindan Rangarajan, Keith Weninger, John Orban, Anand Srivastava, Mohit Kumar Jolly, Jose N. Onuchic, Vladimir N. Uversky, and Ravi Salgia, Biophysics Reviews (2022). The article can be accessed at https://doi.org/10.1063/5.0080512 .