1. Using long-timescale molecular dynamics simulaitons to investigate protein conformational dynamics, with a focus on signaling proteins such as protein kinases and small GTPases. 

2. Using the Swimming simulation method to investigate protein-small molecule binding and protein-protein binding, to predict the resulting complex structures, and to further model functional large protein assemblies.

3. To develope methodologies in computer-aided drug discovery based molecular dynamics in combination with AI and other computational tools, with a focus on the so-called undruggable targets.  

Swimming Simulation Method:

2011：Pioneered the Swimming simulation and recapitulated the process of drug binding with Src kinase 《JACS》

2020：Predicted the complex structure of an EGFR inhibitor osimertinib with EGFR kinase using swimming and corrected the artifact in the existing crystal structure 《Journal of Medicinal Chemistry》

2022：Recapitulated the process of a small molecule inducing while binding at a cryptic binding site using swimming simulations《PLOS Computational Biology》

2023：Recapitulated the process of imatinib binding to Abl kinase and inducing a large conformational change 《Nature Communication》

Simulation-based Prediction of Protein-Protein Complex Structures

2013：Constructed full-length structural models of EGFR in its active and inactive forms and revealed the mechanism of cross-membrane signal transduction 《Cell》

2014：Predicted the JAK2 kinase-pseudokinase complex structrue, which was proven by later emerged crystal structures 《Nature Structure & Molecular Biology》

2015：Predicted the EGFR multimer structure and its role in EGFR signaling  《Nature Communication》

2021：Predicted the structure of the Ras-Raf signalosome and analyzed its functional characteristics《Nature Structure & Molecular Biology》

Protein Conformational Dynamics

2012：Revealed the molecular mechanism underlies the oncogenicity of lung cancer mutations of EGFR kinase《Cell》

2009：Identified the role of the DFG motif that's conserved for protein kinases as an electrostatic sensor and a switch of the kinase conformational states in kinase catalytic cycles 《PNAS》

2013：Revealed the molecular process of kinase deactivation《PNAS》

2015：Identified the conserved allosteric network of protein tyrosine kinases that coordinates their ATP and substrate binding sites《Nature Communication》

1. Zhou H.X.# *, Shan Y.B*. Prediction of protein interaction sites from sequence profile and residue neighbor list. Proteins: Structure, Function, and Genetics . August 2001.

2. Shan Y.B.# *, Klepeis J.L., Eastwood M.P., Dror R.O., Shaw D.E. Gaussian split Ewald: A fast Ewald mesh method for molecular simulation. J. Chem. Phys.. February 2005.

3. Shan Y.B.*, Seeliger M.A., Eastwood, M.P., Frank F., Xu H.F., Jensen M.Ø, Dror R.O., Kuriyan J., Shaw D.E#. A conserved protonation-dependent switch controls drug binding in the Abl kinase. Proceedings of the National Academy of Sciences . Janurary 2009.

4. Shaw D.E.# *, Maragakis P., Lindorff-Larsen K., Piana S., Dror R.O., Eastwood M.P., … Shan Y.B., Wriggers W. Atomic-Level Characterization of the Structural Dynamics of Proteins. Science. October 2010.

5. Shan Y.B.*, Kim E., Eastwood M.P., Seeliger M.A., Shaw D.E#. How does a drug molecule find it target binding site. Journal of the American Chemical Society. May 2011.

6. Dror R.O.*, Pan A.C.*, Arlow D.H.,* Borhani D.W., Maragakis P., Shan Y.B., Xu H., Shaw D.E#. Pathway and mechanism of drug binding to G protein–coupled receptors. Proceedings of the National Academy of Sciences . August 2011.

7. Shan Y.B.# *, Eastwood M.P., Kim E., Zhang X.W., Jumper J., Kuriyan J., Shaw D.E#. Oncogenic Mutations Counteract Intrinsic Disorder in the EGFR Kinase and Promote Receptor Dimerization. Cell. May 2012.

8. Arkhipov A.*, Shan Y.B.#, Das R., Endres N.F., Eastwood M.P., Wemmer D.E., Kuriyan J., Shaw D.E. Architecture and membrane interactions of the EGF receptor. Cell . Janurary 2013.

9. Shan Y.B.# *, Arkhipov A., Kim E.T., Pan A.C., Shaw D.E#. Transitions to catalytically inactive conformations in EGFR kinase. Proceedings of the National Academy of Sciences. April 2013.

10. Arkhipov A.*, Shan Y.B.#, Eric T. Kim, Ron Dror, Shaw D.E#. Her2 activation mechanism reflects evolutionary preservation of asymmetric ectodomain dimers in the human EGFR family. eLIFE. July 2013.

11. Arkhipov A.*, Shan Y.B.#, Kim E.T., Shaw D.E#. Membrane Interaction of Bound Ligands Contributes to the Negative Binding Cooperativity of the EGF Receptor.PLOS Computational Biology. July 2014.

12. Shan Y.B.# *, Gnanasambandan K., Ungureanu D., Kim E.T., Hammarén H., Yamashita K., Silvennoinen O., Shaw D.E.#, Hubbard S.R#. Molecular basis for pseudokinase-dependent autoinhibition of JAK2 tyrosine kinase. Nature Structural & Molecular Biology. June 2014.

13. Foda Z.H.*, Shan Y.B.# *, Kim E.T., Shaw D.E.#, Seeliger M.A#. A dynamically coupled allosteric network underlies binding cooperativity in Src kinase. Nature Communication. January 2015.

14. Needham, S. R.*, Roberts, S. K., Arkhipov, A., Mysore, V. P., Tynan, C. J., … Shan, Y. B.#, Martin-Fernandez, M. L#. EGFR oligomerization organizes kinase-active dimers into competent signalling platforms. Nature Communications. November 2015.

15. Yan, X.E.*, Ayaz, P.*, Zhu, S. J., Zhao, P., Liang, L., Zhang, C. H., Shan, Y. B.#, Yun, C. H#.. Structural basis of AZD9291 selectivity for EGFR T790M. Journal of Medicinal Chemistry. July 2020.

16. Mysore, V.P.*, Zhou, Z.W.*, Ambrogio, C.*, Li, L., Kapp, J.N., Lu, C., Shan Y.B.#, Shaw, D.E#. A structural model of a Ras–Raf signalosome. Nature Structural & Molecular Biology. October 2021.

17. Liu, Y.*, Ke, P., Kuo, Y. C., Wang, Y., Zhang, X., Song, C., Shan, Y. B#. A putative structural mechanism underlying the antithetic effect of homologous RND1 and RhoD GTPases in mammalian plexin regulation. Elife. June 2021.

18. Shan, Y. B.# *, Mysore, V. P., Leffler, A. E., Kim, E. T., Sagawa, S., Shaw, D. E#. How does a small molecule bind at a cryptic binding site. PLoS Computational Biology. March 2022.

19. Mingione, V.R.*, Foda Z.H, Paung Y.T., Philipose H., Rangwala A.M., Shan, Y.B.# Markus, M.A#. Validation of an allosteric binding site of Src kinase identified by unbiased ligand binding simulations. Journal of Molecular Biology. September 2022.

20. Ayaz, P.*, Lyczek, A., Paung, Y.T. , Mingione, V.R., Iacob, I.E., Engen. J.R., Seeliger, M.A., Shan, Y.B.#, Shaw D.E#. Structural mechanism of a drug-binding process involving a large conformational change of the protein target. Nature Communication. April 2023.