Viruses represent a serious public health threat and millions of people die every year from viral diseases. In an effort to prevent and combat viral infection, researchers worldwide are endeavoring to develop vaccines and drug-based treatments, particularly targeting virus capsids.

All-atom description of virus capsids has proven to be extremely valuable in accurately characterizing protein-protein interfaces and in revealing novel interactions between capsids and host factors / drug molecules. Here, innovations in computational modeling and simulation techniques will enable the study of (1) the effect of drug molecules on virus capsids and (2) the dynamic structure of RNA inside capsids.


A central challenge in the simulation of virus capsids (10-100 million atoms) consists in capturing their long-timescale dynamics. Large-scale MD simulations will be accelerated with the performance enhancement provided by petascale/exascale computing (TRD1) to extend current studies of complete capsids into the multi microsecond regime. Another key challenge to accurately describe the interactions between capsids and drug molecules is the inability of current force-fields to account for atomic polarizability. In response, NAMD will extend the use of polarizable forec fields (TRD1), such as the Drude oscillator model to systems with more than 10~million atoms. Furthermore, VMD will develop ffTK for Drude force field (TRD2) for routine parameterization of small-molecule drugs. A long-standing challenge in the computational study of virus capsids is the ability to account for the effects of RNA, as well as divalent cations, like magnesium (Mg2+), which are crucial for the structural integrity and biological activity of RNA; polarizable force field (TRD1) capabilities implemented in NAMD will also improve the modeling of interactions with divalent cations. To enable the inclusion of RNA in capsid simulations, a data-guided RNA modeling (TRD2) framework will be developed to incorporate expanded MDFF support for experimental data (TRD3) into MDFF calculations. Density map segmentation and manipulation (TRD2) tools coupled with advanced display and VR headsets (TRD2) will enable placement of RNA into the cryo-EM density. A further challenge in capsid simulations is presented by the inability to accurately account for the effects of environmental pH. A novel constant-pH (TRD1) algorithm will be extended to multi-million atom systems in tandem with the development of new visualization tools for constant-pH simulation and visualization (TRD2).


The study of virus capsids will build upon the Center's previous work on capsid structure and dynamics of the human immunodeficiency virus (HIV), hepatitis B virus (HBV), and other viruses. With NAMD's performance enhancements (TRD1), whole virus capsids will be simulated for several microseconds employing polarizable force fields. Further development to parameterize drug molecules using the ffTK for Drude (TRD2) and visualization of Drude simulations (TRD2) will enable the study of novel capsid-drug interactions of HIV and HBV with the input of experimental data such as cryo-EM (Zhang, Zlotnick), X-ray crystallography (Sarafianos, Zlotnick) and NMR (Gronenborn, Polenova). Atomic models of viral capsids at multiple pHs will be derived using the constant pH features developed by both TRD1 and TRD2 with experimental restraints derived from cryo-EM (Zhang, Zlotnick) and NMR (Polenova, Gronenborn). The described advances will enable investigation of the role of pH and drug binding in capsid assembly and maturation. The new RNA modeling (TRD2) technologies, which will be developed in collaboration with (Hofacker), will enable modeling of the pregenomic RNA of HBV by incorporating cryo-EM restraints (Zlotnick). Biochemical and genetic data (ZlotnickAiken, Craven) will then be employed to validate the structural models and simulation predictions obtained.

Publications Database
  • All-atom molecular dynamics of virus capsids as drug targets. Juan R. Perilla, Jodi A. Hadden, Boon Chong Goh, Christopher G. Mayne, and Klaus Schulten. Journal of Physical Chemistry Letters, 7:1836-1844, 2016.
  • Molecular architecture of the retroviral capsid. Juan R Perilla and Angela M Gronenborn. Trends in Biochemical Sciences, 41:410-420, 2016.
  • Contributions of charged residues in structurally dynamic capsid surface loops to Rous sarcoma virus assembly. Katrina Heyrana, Boon Chong Goh, Juan Roberto Perilla, Tam-Linh N. Nguyen, Matthew R. England, Maria C. Bewley, Klaus Schulten, and Rebecca Craven. Journal of Virology, 90:5700-5714, 2016.
  • Flexibility coexists with shape persistence in cyanostar macrocycles. Yun Liu, Abhishek Singharoy, Christopher G. Mayne, Arkajyoti Sengupta, Krishnan Raghavachari, Klaus Schulten, and Amar H. Flood. Journal of the American Chemical Society, 138:4843-4851, 2016.
  • Atomic modeling of an immature retroviral lattice using molecular dynamics and mutagenesis. Boon Chong Goh, Juan R. Perilla, Matthew R. England, Katrina J. Heyrana, Rebecca C. Craven, and Klaus Schulten. Structure, 23:1414-1425, 2015.
  • Mature HIV-1 capsid structure by cryo-electron microscopy and all-atom molecular dynamics. Gongpu Zhao, Juan R. Perilla, Ernest L. Yufenyuy, Xin Meng, Bo Chen, Jiying Ning, Jinwoo Ahn, Angela M. Gronenborn, Klaus Schulten, Christopher Aiken, and Peijun Zhang. Nature, 497:643-646, 2013.
  • Atomic model of rabbit hemorrhagic disease virus by cryo-electron microscopy and crystallography. Xue Wang, Fengting Xu, Jiasen Liu, Bingquan Gao, Yanxin Liu, Yujia Zhai, Jun Ma, Kai Zhang, Timothy S. Baker, Klaus Schulten, Dong Zheng, Hai Pang, and Fei Sun. PLoS Pathogens, 9:e1003132, 2013. (14 pages).
  • Dynamic allostery governs cyclophylin A-HIV capsid interplay. Manman Lu, Guangjin Hou, Huilan Zhang, Christopher L. Suiter, Jinwoo Ahn, In-Ja L. Byeon, Juan R. Perilla, Christopher J. Langmead, Ivan Hung, Peter L. Gor'kov, Zhehong Gan, William Brey, Christopher Aiken, Peijun Zhang, Klaus Schulten, Angela M. Gronenborn, and Tatyana Polenova. Proceedings of the National Academy of Sciences, USA, 112:14617-14622, 2015.
  • Elucidating the mechanism behind irreversible deformation of viral capsids. Anton Arkhipov, Wouter H. Roos, Gijs J. L. Wuite, and Klaus Schulten. Biophysical Journal, 97:2061-2069, 2009.
  • Stability and dynamics of virus capsids described by coarse-grained modeling. Anton Arkhipov, Peter L. Freddolino, and Klaus Schulten. Structure, 14:1767-1777, 2006.
  • Molecular dynamics simulations of the complete satellite tobacco mosaic virus. Peter L. Freddolino, Anton S. Arkhipov, Steven B. Larson, Alexander McPherson, and Klaus Schulten. Structure, 14:437-449, 2006.