Modeling RNA 3D structure using experimental constraints

RNA structure determination is one of the major challenges in structural biology. Many RNAs are not amenable to high-resolution structure characterization by either x-ray or NMR methods because of their conformational flexibility or large size. Recently, novel computational methods to determine RNA structures have begun to emerge, but have often been limited to small RNAs with simple topologies due to either sampling problems or inaccuracy in force field. We developed a discrete molecular dynamics (DMD)-based RNA modeling approach, which allowed robust recapitulation of 3D structure of small RNA structures (< 50 nts). To fold large RNAs with complex 3D structures, we proposed to incorporate experimentally-derived structural information into modeling. Using various types experimentally-derived structural information to bias DMD simulations, we were able to recapitulate 3D structure of RNAs with complex topologies and lengths up to 230 nts. We expect a broad application of our experimentally-driven RNA modeling approach for generating robust structural hypotheses that are useful for guiding explorations of structure-function relationships in RNA.


19. Gumna J, Antczak M, Adamiak RW, Bujnicki JM, Chen SJ, Ding F, Ghosh P, Li J, Mukherjee S, Nithin C, Pachulska-Wieczorek K, Ponce-Salvatierra A, Popenda M, Sarzynska J, Wirecki T, Zhang D, Zhang S, Zok T, Westhof E, Miao Z, Szachniuk M, Rybarczyk A., “Computational Pipeline for Reference-Free Comparative Analysis of RNA 3D Structures Applied to SARS-CoV-2 UTR Models”, International Journal of Molecular Sciences, doi: 10.3390/ijms23179630 (2022)

18. J. Ma, N. Saikia, S. Godar, G.L. Hamilton, F. Ding*, J. Alper*, H. Sanabria*, “Ensemble Switching Unveils a Kinetic Rheostat Mechanism of the Eukaryotic Thiamine Pyrophosphate Riboswitch”, RNA, 27(7): 771–790 (2021) doi: 10.1261/rna.075937.120

17. Miao Z, Adamiak RW, Antczak M, Boniecki MJ, Bujnicki JM, Chen SJ, Cheng CY, Cheng Y, Chou FC, Das R, Dokholyan NV, Ding F, Geniesse C, Jiang Y, Joshi A, Krokhotin A, Magnus M, Mailhot O, Major F, Mann TH, Piatkowski P, Pluta R, Popenda M, Sarzynska J, Sun L, Szachniuk M, Tian S, Wang J, Wang J, Watkins AM, Wiedemann J, Xiao Y, Xu X, Yesselman JD, Zhang D, Zhang Y, Zhang Z, Zhao C, Zhao P, Zhou Y, Zok T, Zyla A, Ren A, Batey RT, Golden BL, Huang L, Lilley DM, Liu Y, Patel DJ, Westhof E., “RNA-Puzzles Round IV: 3D structure predictions of four ribozymes and two aptamers”, RNA, in press (2020) doi: 10.1261/rna.075341.120

16. Williams, B., Zhao, B., Tandon, A., Ding, F., Weeks, K. M., Zhang, Q., and Dokholyan, N. V. “Structure modeling of RNA using sparse NMR constraints”, Nucleic Acids Research, in press (2017) doi: 10.1093/nar/gkx1058

15. Miao, Z., Adamiak, R. W., Antczak, M., Batey, R. T., Becka, A. J., Biesiada, M., Boniecki, M. J., Bujnicki, J., Chen, S. J., Cheng, C. Y., Chou, F. C., Ferré-D’Amaré A. R., Das, R., Dawson W. K., Ding, F., Dokholyan, N. V., Dunin-Horkawicz, S., Geniesse, C., Kappel, K., Kladwang, W., Krokhotin, A., Lach, G. E., Major, F., Mann, T. H., Magnus, M., Pachulska-Wieczorek, K., Patel, D. J., Piccirilli, J. A., Popenda, M., Purzycka, K. J., Ren, A., Rice, G. M., Santalcia, J. Jr., Sarzynska, J., Szachniuk, M., Tandon, A., Trausch, J. J., Tian, S., Wang, J., Weeks, K. M., Williams B. 2nd, Xiao, Y., Xu, X., Zhang, D., Zok, T., and Westhof, E. “RNA-Puzzles Round III: 3D RNA structure prediction of five riboswitches and one ribozyme”, RNA, in press (2017) [link]

14. Miao Z, Adamiak RW, Blanchet MF, Boniecki M, Bujnicki JM, Chen SJ, Cheng C, Chojnowski G, Chou FC, Cordero P, Cruz JA, Ferré-D’amaré AR, Das R, Ding F, Dokholyan NV, Dunin-Horkawicz S, Kladwang W, Krokhotin A, Lach G, Magnus M, Major F, Mann TH, Masquida B, Matelska D, Meyer M, Peselis A, Popenda M, Purzycka KJ, Serganov A, Stasiewicz J, Szachniuk M, Tandon A, Tian S, Wang J, Xiao Y, Xu X, Zhang J, Zhao P, Zok T, Westhof E., “RNA-Puzzles Round II: assessment of RNA structure prediction programs applied to three large RNA structures”, RNA, in press, (2015) [download]

13. P. Toran, I. Smolina, H. Driscoll,F. Ding, Y.J. Sun, C.R. Cantor, and N. Broude, “Labeling native bacterial RNA in live cells”, Cell Research, 24(7):894-7 (2014)

12. Homan, P., Tandon, A., Rice, G. M., Ding, F., Dokholyan, N. V., and Weeks, K. M. “RNA tertiary structure analysis and refinement by 2′-hydroxyl molecular interference”, Biochemistry, 53(43):6825-33 (2014)

11. Ramachandran, S., Ding, F., Weeks, K., and Dokholyan, N. V. “Statistical analysis of SHAPE-directed RNA secondary structure modeling”, Biochemistry, in press (2013)

10. D.I. Cole, J.D. Legassie, L.N. Bonifacio, V.G. Sekaran, F. Ding, N.V.  Dokholyan & M. B. Jarstfer, “New Models of Tetrahymena Telomerase RNA from Experimen- tally Derived Constraints and Modeling”, JACS, in press (2012)[download]

9. F. Ding, C. Lavendar, K.M. Weeks, and N.V. Dokholyan, “Three-Dimensional RNA Structure Refinement by Hydroxyl Radical Probing”, Nature Methods, 9(6):603-608 (2012)[download]
*Accompanied by a news and review paper: Behrouzi, R. and Woodson, S.R., “Rendering RNA in 3D”, Nature Methods, 9(6):552-3 (2012)

8. Cruz, J. A., Blanchet, M-F., Boniecki, M., Bujnicki, J. M., Chen, S-J., Cao, S., Das, R., F. Ding, Dokholyan, N. V., Flores, S. C., Lavender C. A., Lisi, V., Major, F., Mikolajczak, K., Philips, A., Puton, T., Santalucia, J., Siyenji, F., Hermann, T., Rother, K., Rother, M., Serganov, S., Skorupski, M., Soltysinski, T., Sripakdeevong, P., Tuszynska, I., Weeks, K. M., Waldsich, C., Wildauer, M., Leontis, N. B. and Westhof, E. “RNA-Puzzles: A CASP-like evaluation of RNA three-dimensional structure prediction”, RNA, 18:610-625[download] (2012)

7. F. Ding. and Dokholyan, N. V., “RNA three-dimensional structure determination using experimental constraints”, in “RNA Nanotechnology and Therapeutics” edited by Dr. Peixuan Guo, in press, (2012)

6. F. Ding and Dokholyan N.V., “Multiscale modeling of RNA Structure and Dynamics” in “RNA 3D Structure Analysis and Prediction”, Edited by Leontis, N. and Westhof, E. Springer, 2012 [download]

5. C. Lavender, F. Ding, Dokholyan, N.V., K.M. Weeks, “Robust and Generic RNA Modeling Using Inferred Constraints: A Structure for the Hepatitis C Virus IRES Pseudoknot Domain, Biochemistry, 49:4931-4933 (2010)[download]

4. C. Hajdin, F. Ding, N. V. Dokholyan, and K. M. Weeks, “How good is that RNA tertiary structure prediction?” RNA, 16:1340-1349 (2010)[download][service]

3. C. M. Gherghe, C. W. Leonard, F. Ding, N. V. Dokholyan, and K. M. Weeks, “Native-like RNA tertiary structures using a sequence-encoded cleavage agent and refinement by discrete molecular dynamics” Journal of the American Chemical Society , 131:2541-2546(2009)[download]

2. S. Sharma, F. Ding, and N. V. Dokholyan, “iFoldRNA: Three-dimensional RNA structure prediction and folding” Bioinformatics, 24:1951-1952 (2008) [download] [service]

1. F. Ding, S. Sharma, P. Chalasani, V. V. Demidov, N. E. Broude, and N. V. Dokholyan, “Large scale simulations of 3D RNA folding by discrete molecular dynamics: From structure prediction to folding mechanisms” RNA, 14: (2008) [download]