ORIGINAL RESEARCH article
Front. Chem.
Sec. Theoretical and Computational Chemistry
ESM3-Driven Hybrid Design of a Hemoglobin Variant with Enhanced Functionality and Structural Stability using Protein Language Model
1. ITMO University, Saint Petersburg, Russia
2. Julius-Maximilians-Universitat Wurzburg, Würzburg, Germany
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Abstract
This study presents a hybrid computational pipeline integrating rational protein design with the ESM3 multimodal generative model to validate a known high-oxygen-affinity hemoglobin (Hb) variant (Hb Fort de France, α45[CD3]His→Arg). Using structural homology to the Hb heme-binding site, we generated an esmHb model with the targeted His45Arg substitution via ESM3. Analyses through integrated computational methods, including Monte Carlo and molecular dynamics simulations, molecular docking, FoldX, MM-GBSA/PBSA, and DFT revealed enhanced structural stability, stronger heme binding (MM-GBSA ΔG: -29.28 vs. -21.75 kcal/mol; MM-PBSA: -64.14 vs. -51.00 kcal/mol), improved subunit interactions, and more favorable oxidation thermodynamics (ΔE improvement: 23.2 kcal/mol) compared to wild-type Hb. These results suggest the utility of the ESM3 model for precise benchmarking and function-preserving engineering of therapeutically relevant proteins like optimized Hb for oxygen therapeutics.
Summary
Keywords
Computational Protein Design, DFT calculations, Hemoglobin, molecular dynamics, Monte Carlo simulation, Myoglobin, oxygen affinity, protein language model
Received
02 June 2026
Accepted
31 July 2026
Copyright
© 2026 Shityakov, Novikov, Skorb and Dandekar. 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: Sergey Shityakov
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.