Deans’ Summer Research Fellowship (DSRF) Story: Shrey Goel

Author: Shrey Goel

What was your major research question for the DSRF project and where do you hope this project will go?

My main research question was whether diffusion-based protein language models could be adapted for de novo membrane protein design, a historically difficult problem due to the scarcity of structural data and the unique constraints of transmembrane (TM) regions. Over the summer, I developed MeMDLM, a fine-tuned diffusion model with per-token guidance (PET) to generate realistic membrane protein sequences while controlling structural features like TM density. I discovered that MeMDLM not only produces sequences with properties similar to those of natural membrane proteins but also outperforms existing state-of-the-art baselines in tasks such as motif scaffolding and residue solubilization. Moving forward, I hope to extend this framework to more diverse membrane topologies (e.g., β-barrels), integrate structural feedback more directly, and experimentally validate a larger set of generated sequences to further bridge the gap between computational and wet-lab protein design.

What challenges did you encounter during your research and how did you work through these difficulties?

A key challenge was the limited availability of experimentally validated membrane protein structures, which made structural training and benchmarking difficult. To address this, I relied heavily on sequence-based metrics (e.g., TM residue density, BLOSUM scores, entropy) and complemented them with predictive tools like DeepTMHMM and ESMFold. Another difficulty was balancing computational tractability with model complexity; I resolved this by selectively fine-tuning layers of a large pretrained model rather than training from scratch, which preserved general protein knowledge while biasing toward membrane-specific
features.

What sparked your interest in this field?

Taking the course BME/COMPSCI 590: Generative AI in Protein Design taught by Dr. Pranam Chatterjee in the Spring 2024 semester. Dr. Chatterjee is now a faculty member at The University of Pennsylvania.

Curious about DSRF?

This project was made possible through the Deans’ Summer Research Fellowship (DSRF)—a unique opportunity for rising juniors and seniors in the Trinity College of Arts & Sciences to pursue funded summer research full-time!