Abstract

Protein structures fold from primary amino acid sequences to secondary structures, and further to tertiary and quaternary structures, ultimately determining their functions. Understanding these sequence-to-structure-to-function relationships provides fundamental insights into protein functions in cells. Simultaneously, it enables us to create/engineer artificial proteins with specific three-dimensional structures, thereby tailoring functions. One bottom-up approach to this is designing peptides to reconstitute minimal protein structures and analyse them. Despite recent significant advances in computational design of water-soluble proteins, the design of membrane peptides and proteins remains a challenging task. The primary challenge arises from the dynamic interactions between water,
lipids, and amino acid residues, which often lead to undesired substates for the designed structures.

To address this challenge, we selected one of the most fundamental membrane protein structures, α-helical peptide channels and pores, and adopted design cycles for optimization: computational design of amino acid sequences; peptide synthesis and protein biophysics, including real-time single-molecule measurement in membrane; prediction of structural dynamics by molecular dynamics simulations; and redesign of amino acid sequences. Through this design process, we
successfully obtained stable peptide assemblies and shed light on how to control their structural dynamics. These results will open a new door to design more complex membrane proteins for applications such as biomaterials including biosensors and filters, and modules for artificial cells.

References

1) A. Niitsu and Y. Sugita Phys. Chem. Chem. Phys. 2023, 25, 3595–3606
2) A.J. Scott†, A. Niitsu†, H.T. Kratochvil, E.J.M. Lang, J.T. Sengel, W.M. Dawson, K.R. Mahendran, M. Mravic, A.R. Thomson, L.R. Brady, L. Liu, A.J.
Mulholland, H. Bayley, W.F. DeGrado, M.I. Wallace, and D.N. Woolfson Nat. Chem., 2021, 13, 643–650
3) K.R. Mahendran†, A. Niitsu†, L. Kong, R.B. Session, A.R. Thomson, D.N. Woolfson, and H. Bayley Nat. Chem. 2017, 9, 411–419
†contributed equally

Brief CV

2012 PhD in Science (Department of Chemistry, the University of Tokyo)
2012–2016 Research Associate (University of Bristol)
2016–2022 Postdoctoral Researcher, SPDR Fellowship, JSPS Fellowship (RIKEN)
2022–present JST PRESTO Researcher (RIKEN)