Accurate de novo design of peptides from programming biophysical landscape

Authors

Li, M., Liu, Y., Zhong, J., Shi, X., Zheng, J., Wang, K., Cui, Y., Cheng, C., Li, S., Kong, X., Li, S., Xv, M., Zhu, C., Lan, X., Yang, H., Chang, K., An, Z., Wan, S., Yang, X., Shen, Q., Xu, H. E., Wang, Z., Liu, L., Zhuang, Y., Ma, J., Zhang, J.

Abstract

Peptides regulate virtually every cellular process and emerge as transformative modalities in bioengineering and therapeutics. However, the de novo design of functional peptides remains challenging, as peptide--protein interactions are governed by delicate and dynamic biophysics that are difficult to model, and experimental datasets are scarce. Here we present NeoPep, a generative deep-learning framework that encodes biophysical principles to accurately design functional peptides de novo. By integrating over 5 million peptide--protein complexes spanning experimentally determined, sequence mimics, and structure ensembles, NeoPep learns the complex biophysical landscape governing peptide function and enables its programmable control. In prospective application across 10 diverse and challenging targets, NeoPep generated potent peptide binders, agonists, and antagonists with hit rates of 12.5--66.7%, even in the absence of defined binding sites or structure information. Beyond de novo co-design, NeoPep supports standalone structure or sequence redesign, readily discriminating subtle context differences. In the structure redesign mode, it generates highly selective peptides with atomic-level conformational accuracy (C RMSD < 2.0 [A] to our solved cryo-EM structure). This structural precision circumvents the need for experimental structure determination, further accelerating iterative sequence redesign to yield a 43.3-fold improvement in potency. These findings establish a general framework for translating biophysical principles into actionable peptide functions, with broad implications for basic research, bioengineering, and medicine.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 11 Jun 2026.

Stats

1-terrible, 9-excellent. How would you rate this preprint? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.