Skip to main content

ORIGINAL RESEARCH article

Front. Mater.
Sec. Biomaterials and Bio-Inspired Materials
Volume 11 - 2024 | doi: 10.3389/fmats.2024.1436379

Accurate informatic modeling of tooth enamel pellicle interactions by training substitution matrices with Mat4Pep

Provisionally accepted
Jeremy H. Keeper Jeremy H. Keeper 1*Jong Seto Jong Seto 1,2,3*Ersin E. Oren Ersin E. Oren 4Orapin V. Horst Orapin V. Horst 1*Ling-Hong Hung Ling-Hong Hung 5Ram Samudrala Ram Samudrala 6
  • 1 University of California, San Francisco, San Francisco, United States
  • 2 Arizona State University, Tempe, Arizona, United States
  • 3 The Molecular Foundry, Berkeley Lab (DOE), Berkeley, California, United States
  • 4 TOBB University of Economics and Technology, Ankara, Ankara, Türkiye
  • 5 University of Washington Tacoma, Tacoma, Washington, United States
  • 6 University at Buffalo, Buffalo, New York, United States

The final, formatted version of the article will be published soon.

    Extracellular matrices direct the formation of mineral constituents into self-assembled mineralized tissues. We investigate the protein and mineral constituents to better understand the underlying mechanisms that lead to mineralized tissue formation. Specifically, we study the protein-hydroxyapatite interactions that govern the development and homeostasis of teeth and bone in the oral cavity. Characterization would enable improvements in the design of peptides to regenerate mineralized tissues and control attachments such as ligaments and dental plaque. Progress has been limited because no available methods produce robust data for assessing organic-mineral interfaces. We show that tooth enamel pellicle peptides contain subtle sequence similarities that encode hydroxyapatite binding mechanisms, by segregating pellicle peptides from control sequences using our previously developed substitution matrix-based peptide comparison protocol with improvements. Sampling diverse matrices, adding biological control sequences, and optimizing matrix refinement algorithms improves discrimination from 0.81 to 0.99 AUC in leave-one-out experiments. Other contemporary methods fail on this problem. We find hydroxyapatite interaction sequence patterns by applying the resulting selected refined matrix ("pellitrix") to cluster the peptides and build subgroup alignments. We identify putative hydroxyapatite maturation domains by application to enamel biomineralization proteins and prioritize putative novel pellicle peptides identified by In stageTip (iST) mass spectrometry. The sequence comparison protocol outperforms other contemporary options for this small and heterogeneous group and is generalized for application to any group of peptides. As a result, this platform has broad impacts on peptide design with direct applications to microbiology, biomaterial design, and tissue engineering.

    Keywords: Pellicle, Organic-mineral interface, Biomineralization, Oral Health, computational modeling methods

    Received: 22 May 2024; Accepted: 17 Oct 2024.

    Copyright: © 2024 Keeper, Seto, Oren, Horst, Hung and Samudrala. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Jeremy H. Keeper, University of California, San Francisco, San Francisco, United States
    Jong Seto, University of California, San Francisco, San Francisco, United States
    Orapin V. Horst, University of California, San Francisco, San Francisco, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.