3D Molecular Modeling Software Enhances Mechanobiological Nanofibril Therapy

Designed to Cure

An illustration of cancer spreading via metastasis which new mechanobiological research seeks to inhibit. Source: Jane Hurd, National Cancer Institute, Wikimedia Commons

Cancer metastasis might soon meet its match if new cervical cancer research from the Okinawa Institute of Science and Technology Graduate University (OIST) can be generalized to multiple types of tumor cells. To make headway on the issue of metastasis—which was previously considered untouchable1—researchers from OIST described an octahedral polypeptide net that can hone in to markers on the lipid rafts of tumor cell membranes and pin them down.2 Pinned groups of cancer cells can’t bud off into the bloodstream and spread the cancer elsewhere in the body via metastasis, meaning that down the line the net could lead to a massive improvement in patient outcomes. While this research is tremendously exciting, making use of the mechanobiological net in the context of cancers that weren’t studied by the team at OIST will require an extensive amount of biological modeling, simulation and protein engineering.

Cancer cells are like slippery fish

It’s commonly understood that cancer metastasis is “bad,” but even scientists within oncology might not understand the exact mechanism of tumor cell budding that leads to tumors spreading throughout the body or the full consequences which spreading entails. That’s because the most insidious aspects of the process of metastasis, like tumor cells’ ability to seemingly pick their method of cell motility to cause the most damage, aren’t fully understood.3  Furthermore, the exact cause of metastasis initiation within a tumor still evades a concrete scientific consensus.4 5 What is understood is that within patients, metastasis marks a dark and difficult path forward where few treatments remain relevant.

Recognizing the importance of cell migration within metastasis, the researchers at OIST sought to examine the lipid rafts and underlying cytoskeleton of tumor cells, working under the proven assumption that cytoskeletal remodeling is necessary for cell motility and thus metastasis.6 The researchers soon learned that the lipid rafts of cervical and ovarian tumor cells contain recurring glycosylphosphatidylinositol-anchored placental alkaline phosphatase motifs (GPI-anchored PLAPs), which could hypothetically be reactive to a molecule containing ruthenium. Critically, the GPI-anchored PLAPs occur only at points of lipid raft patching, meaning that they’re hinge points for the tumor cell to move and expand.

To attack metastasis by exploiting GPI-anchored PLAPs, researchers next designed a self-assembling nanofibril peptide containing ruthenium as well as fluorescent elements using 3D molecular modeling software. Self assembly means that the nanofibrils localize to the site of the tumor, then saturate all of each tumor cell membrane’s GPI-anchored PLAPs, thus forming a net which the tumor cell and its neighbors can’t escape from. Ingeniously, the researchers designed their self-assembling nanofibril to only expose its binding domains for self-assembly after binding to a GPI-anchored PLAP, meaning that it would be safer to use in the bloodstream of a patient in future trials. Most researchers aspire to have the optimism and clinical foresight to implement solutions like these.

When cancer cells are held tightly against each other by the molecular net, they’re not able to escape to metastasize elsewhere and their functioning at their point of establishment is heavily impaired. As a bonus, researchers also noted that there were some instances of tumor cell motility which resulted in cell lysis as a result of overpressurization caused by being tightly pinned by the nanofibrils. Pinning down tumor cells means that they might even destroy themselves in their most energetic attempts to escape the trap.

Reeling in the net

Generating mechanobiological nets that self assemble at their point of action simply isn’t a result of trial-and-error starting from an initial chemical concept. Instead, researchers used sophisticated biological molecule modeling software to design their candidate molecules before experimentation. Specifically, modeling the self-assembly aspect of their molecules was critical, as the binding of the ruthenium motif to the GPI-anchored PLAP was via a relatively isolated chemical reaction and thus stochastically calculable with high confidence.  

In short, researchers used modeling software to address the following moving parts of their system:

  • The connection between GPI-anchored PLAPs with other patches of the tumor cell’s lipid raft
  • The connection between GPI-anchored PLAPs with the underlying cytoskeleton
  • The electrochemical forces of the lipid raft which might be of opposite polarity to the net-forming peptides, thus preventing binding to the GPI-anchored PLAP
  • The electrochemical forces of the net-forming peptides before binding to the GPI-anchored PLAP
  • The exposure of binding domains in the net forming peptide during and after binding to the GPI-anchored PLAP
  • The electrochemical forces of the exposed binding domains of the net forming peptide, which might potentially push away net forming peptides with non-exposed binding domains
  • The chiral or non chiral binding of net forming peptide binding domains to each other to form the nanofibril macrostructure
  • The electrochemical force of the nanofibril net and its ability to maintain rigidity or elasticity when interacting with the electrochemical force of the tumor cell’s cytoskeleton as they attempt motility to expand outward beyond the boundary of the net

If you’re balking at the amount of biochemistry involved in designing the net forming molecules and ensuring that they can properly self-assemble to durably suppress metastasis, you’re not alone. The sheer depth of the molecular simulations that are required to develop a working solution to cancer metastasis dwarfs even that of most other complicated biological simulations because they have to simulate multiple levels of organization, ranging from the atom-to-atom reactions of the ruthenium binding, to the protein-protein interactions of the binding domains with each other, and culminating in the nanofibril macrostructure’s self-assembly and maintenance of tumor suppression. This kind of research was a distant fantasy no fewer than five or six years ago, but thankfully computer simulations have come great strides since then thanks to improved algorithms and burgeoning computing power.7  If researchers are interested in performing studies similar to the researchers at OIST, they’ll need to equip themselves with a powerful simulation suite to design their molecules before entering the lab.

BIOVIA Designed to Cure is an advanced software solution experience that supports collaborative research driven by organizational knowledge and rigorous analysis. Contact us today to find out how you can use Designed to Cure to join the fight against metastasis.

  1. “Metastasis prevention by targeting the dormant niche.” March 2015, http://www.nature.com/nrc/journal/v15/n4/abs/nrc3910.html
  2. “Patching of Lipid Rafts by Molecular Self-Assembled Nanofibrils Suppresses Cancer Cell Migration.” February 2017, http://www.cell.com/chem/fulltext/S2451-9294(17)30026-8
  3. “Rac and Rho GTPases in cancer cell motility control.” 2010, http://download.springer.com/static/pdf/646/art%253A10.1186%252F1478-811X-8-23.pdf?originUrl=http%3A%2F%2Fbiosignaling.biomedcentral.com%2Farticle%2F10.1186%2F1478-811X-8-23&token2=exp=1495552253~acl=%2Fstatic%2Fpdf%2F646%2Fart%25253A10.1186%25252F1478-811X-8-23.pdf*~hmac=a52fc191b77d5bc018b25bbdbeb151463ae41c3ce556e231662aec0828333826
  4. “The migration ability of stem cells can explain the existence of cancer of unknown primary site. Rethinking metastasis.” 2015, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468332/
  5. “A new hypothesis: some metastases are the result of inflammatory processes by adapted cells, especially adapted immune cells at sites of inflammation.” February 2016, https://f1000research.com/articles/5-175/v1
  6. “Movers and shakers: cell cytoskeleton in cancer metastasis.” July 2014, http://onlinelibrary.wiley.com/doi/10.1111/bph.12704/full
  7. “Stochastic simulation in systems biology.” October 2014, http://www.sciencedirect.com/science/article/pii/S2001037014000403