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  3. The design of functional proteins using tensorized energy calculations

The design of functional proteins using tensorized energy calculations

  • Cell Rep Methods. 2023 Aug 15;3(8):100560. doi: 10.1016/j.crmeth.2023.100560.
Kateryna Maksymenko 1 2,  Andreas Maurer 3 4,  Narges Aghaallaei 5,  Caroline Barry 1 6,  Natalia Borbarán-Bravo 5,  Timo Ullrich 1 2,  Tjeerd M H Dijkstra 1 7 8,  Birte Hernandez Alvarez 1,  Patrick Müller 2,  Andrei N Lupas 1,  Julia Skokowa 5,  Mohammad ElGamacy 1 2 5
Affiliations

Affiliations

  • 1 Department of Protein Evolution, Max Planck Institute for Biology, 72076 Tübingen, Germany.
  • 2 Friedrich Miescher Laboratory of the Max Planck Society, 72076 Tübingen, Germany.
  • 3 Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, 72076 Tübingen, Germany.
  • 4 Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies," Eberhard Karls University, 72076 Tübingen, Germany.
  • 5 Division of Translational Oncology, University Hospital Tübingen, 72076 Tübingen, Germany.
  • 6 Krieger School of Arts and Sciences, Johns Hopkins University, Washington, DC 20036, USA.
  • 7 Department for Women's Health, University Hospital Tübingen, 72076 Tübingen, Germany.
  • 8 Translational Bioinformatics, University Hospital Tübingen, 72072 Tübingen, Germany.
PMID: 37671023 DOI: 10.1016/j.crmeth.2023.100560
Abstract

In protein design, the energy associated with a huge number of sequence-conformer perturbations has to be routinely estimated. Hence, enhancing the throughput and accuracy of these energy calculations can profoundly improve design success rates and enable tackling more complex design problems. In this work, we explore the possibility of tensorizing the energy calculations and apply them in a protein design framework. We use this framework to design enhanced proteins with anti-cancer and radio-tracing functions. Particularly, we designed multispecific Binders against ligands of the epidermal growth factor receptor (EGFR), where the tested design could inhibit EGFR activity in vitro and in vivo. We also used this method to design high-affinity Cu2+ Binders that were stable in serum and could be readily loaded with copper-64 radionuclide. The resulting molecules show superior functional properties for their respective applications and demonstrate the generalizable potential of the described protein design approach.

Keywords

EGFR inhibitor; copper binder; discrete rotamer sampling; energy calculation; protein design.

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