The shape that barely exists

What if the form of a molecule that actually does the work is the one you almost never see?

For decades, molecular design has leaned on a single stable structure, the equivalent of a passport photograph of a protein or peptide. Yet these molecules are not statues. They fold, flex and exchange between many conformations, and some of the states that matter most for biological activity exist only a fraction of the time. Because they are so sparsely populated, they remain invisible to conventional structural methods.

A new study published in the Journal of the American Chemical Society, led by Prof. Dan T. Major and Prof. Jordan H. Chill of the Department of Chemistry at Bar-Ilan University and the Bar-Ilan Institute of Nanotechnology and Advanced Materials (BINA), together with Chen Timsit Shmueli and Miriam Gulman, set out to find those hidden states.

The team studied Hui1, a small synthetic peptide that blocks potassium channels at very low concentrations. Potassium channels are an established target for drug development in autoimmune and neurological disease, and peptides of this class serve as templates for a broader family of candidate therapeutics.

To see every pose the molecule adopts, and not only the most prominent one, the researchers combined parallel-bias metadynamics-metainference simulations with relaxation-dispersion NMR. The simulation proposes the map of accessible conformations; the NMR measurement confirms which of them the molecule genuinely visits in solution.

The result is striking: the conformation that recognizes and binds the channel is not the dominant one, but a rare, transiently populated state.

The implication reaches well beyond this single peptide. A design campaign built on the stable structure alone may be optimizing against the wrong picture, spending time and resources on candidates that were never going to work. The combined computational and experimental approach presented here offers a practical route to identify the functionally relevant conformation in advance.

Congratulations to Chen Timsit Shmueli, Miriam Gulman, Prof. Dan T. Major and Prof. Jordan H. Chill on this contribution to structure-based molecular design.

Read the full paper published in the Journal of the American Chemical Society: https://doi.org/10.1021/jacs.5c22533