Jim L. Zhang

All Publications

• Efficient generation of epitope-targeted antibodies with Germinal. Nature biotechnology Mille-Fragoso, L. S., Driscoll, C. L., Wang, J. N., Dai, H., Widatalla, T., Zhang, J. L., Zhang, X., Rao, B., Feng, L., Hie, B. L., Gao, X. J. 2026

  Abstract

  Obtaining antibodies to specific protein targets is a widely important yet experimentally laborious process. Meanwhile, computational methods for antibody design have been limited by low success rates that require resource-intensive screening. Here we introduce Germinal, a broadly enabling generative pipeline that designs antibodies against specific epitopes with nanomolar binding affinities while requiring only low-n experimental testing. Our method co-optimizes antibody structure and sequence by integrating a structure predictor with an antibody-specific protein language model to perform de novo design of functional complementarity-determining regions onto a user-specified structural framework. When tested against four diverse protein targets, Germinal designed functional antibodies across all targets and binder formats, testing only 43-101 designs for each antigen. Validated designs also exhibited robust expression in mammalian cells and high sequence and structural novelty. We provide open-source code and full computational and experimental protocols to facilitate wide adoption.

  View details for DOI 10.1038/s41587-026-03187-0

  View details for PubMedID 42337361

  View details for PubMedCentralID 431171

• TMEM65 reconstitutes mitochondrial Na + /Ca2+exchange Zhang, J. L., Chang, Y., Feng, L., Tsai, M. CELL PRESS. 2026: 240a

  View details for Web of Science ID 001717247400020

• TMEM65 functions as the mitochondrial Na+/Ca2+ exchanger. Nature cell biology Zhang, J. L., Chang, Y. C., Lai, P. H., Yeh, H. I., Tsai, C. W., Huang, Y. L., Liu, T. Y., Lee, I. C., Foulon, N., Xu, Y., Rao, B., Shih, H. M., Tu, Y. C., Reyes, A. V., Xu, S. L., Feng, L., Tsai, M. F. 2025

  Abstract

  Mitochondria export Ca2+ via Na+/Ca2+ exchange machinery (mito-NCX) to regulate intracellular Ca2+ signalling and mitochondrial Ca2+ homeostasis. TMEM65 has recently been implicated as essential for mito-NCX, but its mechanisms and roles remain unclear. Here we show that TMEM65 depletion severely impairs mito-NCX. TMEM65 is highly expressed in the heart and brain but absent in the liver, correlating with mito-NCX activity in these tissues. Biochemical and functional analyses reveal that TMEM65 forms a homodimer, containing plausible ion-coordinating residues critical for function. Heterologous expression of TMEM65 induces Na+/Ca2+ exchange in cells lacking native mito-NCX activity. Moreover, purified, liposome-reconstituted TMEM65 exhibits key mito-NCX features. We further identify the binding site for CGP-37157, a potent, widely used mito-NCX inhibitor. Finally, TMEM65 deletion elevates mitochondrial Ca2+ and primes mitochondria to permeability transition. These findings firmly establish TMEM65 as the protein mediating mito-NCX, offering a new therapeutic target for diseases associated with mitochondrial Ca2+ dysregulation.

  View details for DOI 10.1038/s41556-025-01721-x

  View details for PubMedID 40691517

  View details for PubMedCentralID 6715724