# Shakhnovich Biophysics Lab - The Shakhnovich Lab currently seeks experimental research assistants for **high-throughput screening** and **protein biophysical characterization**, working closely with the lab’s machine learning team. Offer will be granted on rolling basis until positions are filled. Contact and cc [shakhnovich@chemistry.harvard.ed](mailto:shakhnovich@chemistry.harvard.edu)u. - The Shakhnovich lab is seeking talented students working on the interface of **machine learning,** and protein evolution over the 2026 summer/academic year. See more information [here](https://docs.google.com/document/d/1uWgOcDkZ8Gf7SeFhePf5u3vygDj7DoCF/edit?pli=1#heading=h.1fob9te). Offer will be granted on rolling basis until positions are filled. - The Shakhnovich lab is seeking **experimental** research assistants working on protein folding and conformational dynamics, and their effects on evolution for 2026 summer/academic year. See more information [here](https://docs.google.com/document/d/1wJ0s9z_pI04QGzctw1ZaoZQoYJR2yxxB/edit?usp=sharing&ouid=108673240718481132174&rtpof=true&sd=t). The Shakhnovich lab is accepting PhD and rotational students. Please contact Prof. Shakhnovich via . The Shakhnovich Biophysics Lab works on a broad range of topics from protein folding, functional dynamics, drug discovery to molecular evolution and origins of life. Our approach integrates theoretical, computational and experimental work. Here is a poster that summarize our recent research efforts, also see our [Research page](/pages/research "Research") for more details. ![lab_poster](/sites/g/files/omnuum7291/files/shakhnovich/files/lab_poster_final-1.png) A lecture by Prof. Shakhnovich highlighting research efforts is available [here](https://www.youtube.com/watch?v=vgvBkre4xEM). ![Shakhnovich_Cover](/sites/g/files/omnuum7291/files/styles/hwp_1_1__720x720_scale/public/shakhnovich/files/shakhnovich_cover.jpg?itok=vkqoqV0l) **"Coral Reef" model of active cytoplasm: Protein Quality Control (PQC) shapes fitness effects of mutations**. Components that belong to opposite branches of PQC – chaperonins (GroEL) and ATP-dependent proteases (Lon) – act on equilibrium Molten Globule folding intermediate of an essential protein (DHFR) in *E. coli* cytoplasm. Changes in the chromosomal *folA* gene encoding DHFR were introduced by making point mutations or by replacing the the gene altogether by its orthologs from a range of bacterial species. Relative fitness of the *folA* mutant and orthologous-replacement *E coli* strains is determined by the amount of soluble DHFR in their cytoplasm. The abundance of soluble DHFR is established in dynamic steady-state where production and GroEL-assisted folding is balanced by proteolytic digestion of DHFR in its Molten Globule state by the ATP-dependent protease Lon. ## Recent Publications Download 12 citations download- [BibTeX](/bibcite/export?pager_style=no_pager&number_of_items=12&sort_field=bibcite_year--desc&taxonomy_filters=&&&format=bibtex) - [EndNote X3 XML](/bibcite/export?pager_style=no_pager&number_of_items=12&sort_field=bibcite_year--desc&taxonomy_filters=&&&format=endnote8) - [EndNote 7 XML](/bibcite/export?pager_style=no_pager&number_of_items=12&sort_field=bibcite_year--desc&taxonomy_filters=&&&format=endnote7) - [Endnote tagged](/bibcite/export?pager_style=no_pager&number_of_items=12&sort_field=bibcite_year--desc&taxonomy_filters=&&&format=tagged) - [Marc](/bibcite/export?pager_style=no_pager&number_of_items=12&sort_field=bibcite_year--desc&taxonomy_filters=&&&format=marc) - [PubMedId](/bibcite/export?pager_style=no_pager&number_of_items=12&sort_field=bibcite_year--desc&taxonomy_filters=&&&format=pubmed_id) - [RIS](/bibcite/export?pager_style=no_pager&number_of_items=12&sort_field=bibcite_year--desc&taxonomy_filters=&&&format=ris) ### 2026 Bigot, A., Bhasin, H., Park, C. F., Shakhnovich, E. & Wang, D. [Viral Proteins Reveal Geometry of Protein Language Models](/publication/viral-proteins-reveal-geometry-protein-language-models). (2026) doi:10.48550/arXiv.2606.12609. Bigot, A., Bhasin, H., Park, C. F., Shakhnovich, E. & Wang, D. [Viral Proteins Reveal Geometry of Protein Language Models](/publication/viral-proteins-reveal-geometry-protein-language-models). (2026) doi:10.48550/arXiv.2606.12609. - add\_circle\_outline do\_not\_disturb\_on Abstract - [ descriptionPublisher's Version](http://arxiv.org/abs/2606.12609) Protein language models are trained on highly imbalanced datasets, raising the question of how they represent underrepresented biological sequences. Using viral proteins as a case study across ESM model families, we identify a dominant nativeness axis in... - [ descriptionPublisher's Version](http://arxiv.org/abs/2606.12609) ### 2025 Wang, S., Bitran, A., Samatova, E., Shakhnovich, E. I. & Rodnina, M. , V. [Cotranslational Protein Folding Through Non-Native Structural Intermediates.](/publication/cotranslational-protein-folding-through-non-native-structural-intermediates) *bioRxiv : the preprint server for biology* (2025) doi:10.1101/2025.04.09.648002. Wang, S., Bitran, A., Samatova, E., Shakhnovich, E. I. & Rodnina, M. , V. [Cotranslational Protein Folding Through Non-Native Structural Intermediates.](/publication/cotranslational-protein-folding-through-non-native-structural-intermediates) *bioRxiv : the preprint server for biology* (2025) doi:10.1101/2025.04.09.648002. - add\_circle\_outline do\_not\_disturb\_on Abstract Cotranslational protein folding follows a distinct pathway shaped by the vectorial emergence of the peptide and spatial constraints of the ribosome exit tunnel. Variations in translation rhythm can cause misfolding linked to disease; however, predicting... Mohanty, V. & Shakhnovich, E. I. [Biophysical fitness landscape design traps viral evolution.](/publication/biophysical-fitness-landscape-design-traps-viral-evolution) *bioRxiv : the preprint server for biology* (2025) doi:10.1101/2025.03.30.646233. Mohanty, V. & Shakhnovich, E. I. [Biophysical fitness landscape design traps viral evolution.](/publication/biophysical-fitness-landscape-design-traps-viral-evolution) *bioRxiv : the preprint server for biology* (2025) doi:10.1101/2025.03.30.646233. - add\_circle\_outline do\_not\_disturb\_on Abstract We introduce foundational principles for designing customizable fitness landscapes for proteins. We focus on crafting antibody ensembles to create evolutionary traps which restrict viral fitness enhancement. By deriving a fundamental relationship between... Huot, M., Wang, D., Liu, J. & Shakhnovich, E. [Few-Shot Viral Variant Detection via Bayesian Active Learning and Biophysics.](/publication/few-shot-viral-variant-detection-bayesian-active-learning-and-biophysics) *bioRxiv : the preprint server for biology* (2025) doi:10.1101/2025.03.12.642881. Huot, M., Wang, D., Liu, J. & Shakhnovich, E. [Few-Shot Viral Variant Detection via Bayesian Active Learning and Biophysics.](/publication/few-shot-viral-variant-detection-bayesian-active-learning-and-biophysics) *bioRxiv : the preprint server for biology* (2025) doi:10.1101/2025.03.12.642881. - add\_circle\_outline do\_not\_disturb\_on Abstract The early detection of high-fitness viral variants is critical for pandemic response, yet limited experimental resources at the onset of variant emergence hinder effective identification. To address this, we introduce an active learning framework that... Mondal, S. & Shakhnovich, E. [The Origin of the Ionic-strength Dependent Reentrant Behavior in Liquid-Liquid Phase Separation of Neutral IDPs.](/publication/origin-ionic-strength-dependent-reentrant-behavior-liquid-liquid-phase-separation) *bioRxiv : the preprint server for biology* (2025) doi:10.1101/2025.03.20.644249. Mondal, S. & Shakhnovich, E. [The Origin of the Ionic-strength Dependent Reentrant Behavior in Liquid-Liquid Phase Separation of Neutral IDPs.](/publication/origin-ionic-strength-dependent-reentrant-behavior-liquid-liquid-phase-separation) *bioRxiv : the preprint server for biology* (2025) doi:10.1101/2025.03.20.644249. - add\_circle\_outline do\_not\_disturb\_on Abstract The effect of salt on coacervation of synthetic or biological polyelectrolytes is well-studied. However, recent experiments showed that largely neutral IDPs like FUS also undergo LLPS at physiological salt concentrations, dissolve at higher salt... Sabbarini, I. M. *et al.* [A ribosome-associating chaperone mediates GTP-driven vectorial folding of nascent eEF1A.](/publication/ribosome-associating-chaperone-mediates-gtp-driven-vectorial-folding-nascent-eef1a) *Nature communications* **16**, 1277 (2025). Sabbarini, I. M. *et al.* [A ribosome-associating chaperone mediates GTP-driven vectorial folding of nascent eEF1A.](/publication/ribosome-associating-chaperone-mediates-gtp-driven-vectorial-folding-nascent-eef1a) *Nature communications* **16**, 1277 (2025). - add\_circle\_outline do\_not\_disturb\_on Abstract Eukaryotic translation elongation factor 1A (eEF1A) is a highly abundant, multi-domain GTPase. Post-translational steps essential for eEF1A biogenesis are carried out by bespoke chaperones but co-translational mechanisms tailored to eEF1A folding remain... Arenas, C. D., Alvarez, M., Wilson, R. H., Shakhnovich, E. I. & Ogbunugafor, B. [Protein Quality Control is a Master Modulator of Molecular Evolution in Bacteria.](/publication/protein-quality-control-master-modulator-molecular-evolution-bacteria) *Genome biology and evolution* **17**, (2025). Arenas, C. D., Alvarez, M., Wilson, R. H., Shakhnovich, E. I. & Ogbunugafor, B. [Protein Quality Control is a Master Modulator of Molecular Evolution in Bacteria.](/publication/protein-quality-control-master-modulator-molecular-evolution-bacteria) *Genome biology and evolution* **17**, (2025). - add\_circle\_outline do\_not\_disturb\_on Abstract The bacterial protein quality control (PQC) network comprises a set of genes that promote proteostasis (proteome homeostasis) through proper protein folding and function via chaperones, proteases, and protein translational machinery. It participates in... Chattaraj, A. & Shakhnovich, E. I. [Separation of sticker-spacer energetics governs the coalescence of metastable condensates.](/publication/separation-sticker-spacer-energetics-governs-coalescence-metastable-condensates-0) *Biophysical journal* **124**, 428–439 (2025). Chattaraj, A. & Shakhnovich, E. I. [Separation of sticker-spacer energetics governs the coalescence of metastable condensates.](/publication/separation-sticker-spacer-energetics-governs-coalescence-metastable-condensates-0) *Biophysical journal* **124**, 428–439 (2025). - add\_circle\_outline do\_not\_disturb\_on Abstract Biological condensates often emerge as a multidroplet state and never coalesce into one large droplet within the experimental timespan. Previous work revealed that the sticker-spacer architecture of biopolymers may dynamically stabilize the multidroplet... ### 2024 Chattaraj, A. & Shakhnovich, E. I. [Separation of sticker-spacer energetics governs the coalescence of metastable condensates.](/publication/separation-sticker-spacer-energetics-governs-coalescence-metastable-condensates) *bioRxiv : the preprint server for biology* (2024) doi:10.1101/2023.10.03.560747. Chattaraj, A. & Shakhnovich, E. I. [Separation of sticker-spacer energetics governs the coalescence of metastable condensates.](/publication/separation-sticker-spacer-energetics-governs-coalescence-metastable-condensates) *bioRxiv : the preprint server for biology* (2024) doi:10.1101/2023.10.03.560747. - add\_circle\_outline do\_not\_disturb\_on Abstract Biological condensates often emerge as a multi-droplet state and never coalesce into one large droplet within the experimental timespan. Previous work revealed that the sticker-spacer architecture of biopolymers may dynamically stabilize the multi-droplet... Wang, Y. *et al.* [Entropy Changes in Water Networks Promote Protein Denaturation.](/publication/entropy-changes-water-networks-promote-protein-denaturation) *bioRxiv : the preprint server for biology* (2024) doi:10.1101/2024.06.12.598657. Wang, Y. *et al.* [Entropy Changes in Water Networks Promote Protein Denaturation.](/publication/entropy-changes-water-networks-promote-protein-denaturation) *bioRxiv : the preprint server for biology* (2024) doi:10.1101/2024.06.12.598657. - add\_circle\_outline do\_not\_disturb\_on Abstract For over a century, an explanation for how concentrated ions denature proteins has proven elusive. Here, we report a novel mechanism of protein denaturation driven by entropy changes in water networks. Experiments and simulations show that ion pairs like... Chattaraj, A. & Shakhnovich, E. I. [Multi-condensate state as a functional strategy to optimize the cell signaling output.](/publication/multi-condensate-state-functional-strategy-optimize-cell-signaling-output-0) *Nature communications* **15**, 6268 (2024). Chattaraj, A. & Shakhnovich, E. I. [Multi-condensate state as a functional strategy to optimize the cell signaling output.](/publication/multi-condensate-state-functional-strategy-optimize-cell-signaling-output-0) *Nature communications* **15**, 6268 (2024). - add\_circle\_outline do\_not\_disturb\_on Abstract The existence of multiple biomolecular condensates inside living cells is a peculiar phenomenon not compatible with the predictions of equilibrium statistical mechanics. In this work, we address the problem of multiple condensates state (MCS) from a... Wang, D., Huot, M., Mohanty, V. & Shakhnovich, E. I. [Biophysical principles predict fitness of SARS-CoV-2 variants.](/publication/biophysical-principles-predict-fitness-sars-cov-2-variants-0) *Proceedings of the National Academy of Sciences of the United States of America* **121**, e2314518121 (2024). Wang, D., Huot, M., Mohanty, V. & Shakhnovich, E. I. [Biophysical principles predict fitness of SARS-CoV-2 variants.](/publication/biophysical-principles-predict-fitness-sars-cov-2-variants-0) *Proceedings of the National Academy of Sciences of the United States of America* **121**, e2314518121 (2024). - add\_circle\_outline do\_not\_disturb\_on Abstract SARS-CoV-2 employs its spike protein's receptor binding domain (RBD) to enter host cells. The RBD is constantly subjected to immune responses, while requiring efficient binding to host cell receptors for successful infection. However, our understanding of...