Mark your calendars - Third BMMP Seminar 2026 - 11th September

[Ragothaman Yennamalli]

Dear all,

We will have our third seminar of this season with Dr. Anand Srivastava from IISc Bangalore.

Details of the Seminar:
Title: Morpheus: Investigating fold switching proteins through the lens of machine learning and statistical thermodynamics
Date: 11th September 2026, Friday
Time: 4:00-5:00 PM (India Standard Time)
Format: GMeet: https://tinyurl.com/anandmbu

We look forward to your participation in what promises to be an enlightening and engaging session. Please share them among your network and encourage them to participate.

Abstract: Functionally important metamorphic proteins, which can switch folds between different well folded conformations, are now thought to be widespread. These protein sequences do not obey the classical folding dogma, and the underlying principles that drive their fold-switching behavior is poorly understood. In my talk, I will present two diverse approaches towards understanding the molecular grammar of fold switchers - one based on machine learning and other on thermodynamics principles. In the first part, I will present a new fragment-based classification algorithm from my group, named as Morpheus, which can annotate fold-switching proteins from sequence information across proteomes (https://doi.org/10.1093/bioinformatics/btaf635, https://doi.org/10.64898/2026.08.16.745091). Since
Morpheus server takes in user defined sequences, it can also act as a useful screening tool towards the de novo design and engineering of such proteins through further experimentation. However, rationale de novo design of fold switching proteins will require a thorough understanding of the molecular driving forces leading to their conformational propensities. In the second part of my talk, I will discuss our recent work (https://doi.org/10.1101/2025.10.10.679401) on understanding the thermodynamic design principles that leads to fold-switching behavior in such proteins. As a test case, we considered a recently designed foldswitching protein [John Orban and co-authors, PNAS 2023] that transitions between a 3α fold and α/β fold upon changes in temperature. We performed a detailed thermodynamic analysis on this protein using an advanced and efficient free energy all-atom molecular simulation approach. We find that while 3α fold is stabilized at low temperatures by enthalpic contributions from favorable water-water and protein-water interactions, the transition to the α/β fold at high temperatures is driven by the gain of entropy from the release of ordered water molecules surrounding the 3α conformer into the bulk. Our study elucidates the importance of thinking in terms of entropy-based design in natural systems and provides an integrated machine learning and physics-based framework that can help in the design and engineering of future synthetic and functional metamorphic proteins.

Thanks and Regards,
Raghu

https://groups.google.com/g/bmmp-india

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Ragothaman M Yennamalli, Ph.D.

Associate Professor,

School of Computational and Integrative Sciences.

Jawaharlal Nehru University,

New Delhi - 110067.

https://yennamalli-lab.in/

https://www.jnu.ac.in/content/ragothaman

Indian Ambassador, Biophysical Society USA

Chair, Publications Committee, ISCB USA

Executive Committee Member, APBioNet

Associate Editor, Computational and Structural Biotechnology Journal

Associate Editor, Bioinformatics and Biology Insights

Special Issue Editor, Biophysical Journal

Editorial Board, BMC Bioinformatics

Editorial Board, Scientific Reports

Early Career Researcher Review Board, Protein Science

"When you can do the common things of life in an uncommon way, you will command the attention of the world." -George Washington Carver
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