XSEDE systems Stampede1 and Comet help sample protein folding in bone regeneration study
Some secrets to repair our skeletons might be found in the silky webs of spiders, according to recent experiments guided by supercomputers. Scientists involved say their results will help understand the details of osteoregeneration, or how bones regenerate.
A study found that genes could be activated in human stem cells that initiate biomineralization, a key step in bone formation. Scientists achieved these results with engineered silk derived from the dragline of golden orb weaver spider webs, which they combined with silica. The study appeared September 2017 in the journal Advanced Functional Materials and has been the result of the combined effort from three institutions: Tufts University, Massachusetts Institute of Technology and Nottingham Trent University.
"This work demonstrates a direct link between silk-silica-based biomaterials and intracellular pathways leading to osteogenesis," said study co-author Zaira Martín-Moldes, a post-doctoral scholar at the Kaplan Lab at Tufts University. She researches the development of new biomaterials based on silk. "The hybrid material promoted the differentiation of human mesenchymal stem cells, the progenitor cells from the bone marrow, to osteoblasts as an indicator of osteogenesis, or bone-like tissue formation," Martín-Moldes said.
"Silk has been shown to be a suitable scaffold for tissue regeneration, due to its outstanding mechanical properties," Martín-Moldes explained. It's biodegradable. It's biocompatible. And it's fine-tunable through bioengineering modifications. The experimental team at Tufts University modified the genetic sequence of silk from golden orb weaver spiders (Nephila clavipes) and fused the silica-promoting peptide R5 derived from a gene of the diatom Cylindrotheca fusiformis silaffin.
The bone formation study targeted biomineralization, a critical process in materials biology. "We would love to generate a model that helps us predict and modulate these responses both in terms of preventing the mineralization and also to promote it," Martín-Moldes said.
This work demonstrates a direct link between silk-silica-based biomaterials and intracellular pathways leading to osteogenesis."High performance supercomputing simulations are utilized along with experimental approaches to develop a model for the integrin activation, which is the first step in the bone formation process," said study co-author Davoud Ebrahimi, a postdoctoral associate at the Laboratory for Atomistic and Molecular Mechanics of the Massachusetts Institute of Technology.
Integrin embeds itself in the cell membrane and mediates signals between the inside and the outside of cells. In its dormant state, the head unit sticking out of the membrane is bent over like a nodding sleeper. This inactive state prevents cellular adhesion. In its activated state, the head unit straightens out and is available for chemical binding at its exposed ligand region.
The derived silk–silica chimera they studied weighed in around a hefty 40 kilodaltons. "In this research, what we did in order to reduce the computational costs, we have only modeled the head piece of the protein, which is getting in contact with the surface that we're modeling," Ebrahimi said. "But again, it's a big system to simulate and can't be done on an ordinary system or ordinary computers."
The Computational team at MIT used the molecular dynamics package called Gromacs, a software for chemical simulation available on both the Stampede1 and Comet supercomputing systems. "We could perform those large simulations by having access to XSEDE computational clusters," he said.
Computation combined with experimentation helped advance work in developing a model of osteoregeneration. "We propose a mechanism in our work," explained Martín-Moldes, "that starts with the silica-silk surface activating a specific cell membrane protein receptor, in this case integrin αVβ3." She said this activation triggers a cascade in the cell through three mitogen-activated protein kinsase (MAPK) pathways, the main one being the c-Jun N-terminal kinase (JNK) cascade.
"We are doing a basic research here with our silk-silica systems," Martín-Moldes explained. "But we are helping in building the pathway to generate biomaterials that could be used in the future. The mineralization is a critical process. The final goal is to develop these models that help design the biomaterials to optimize the bone regeneration process, when the bone is required to regenerate or to minimize it when we need to reduce the bone formation."
I got a lot of help from XSEDE resources and people at XSEDE.These results help advance the research and are useful in larger efforts to help cure and treat bone diseases. "We could help in curing disease related to bone formation, such as calcific aortic valve disease or osteoporosis, which we need to know the pathway to control the amount of bone formed, to either reduce or increase it, Ebrahimi said.
"Intracellular Pathways Involved in Bone Regeneration Triggered by Recombinant Silk–Silica Chimeras," DOI: 10.1002/adfm.201702570, appeared September 2017 in the journal Advanced Functional Materials. The National Institutes of Health funded the study, and the National Science Foundation through XSEDE provided computational resources. The study authors are Zaira Martín-Moldes, Nina Dinjaski, David L. Kaplan of Tufts University; Davoud Ebrahimi and Markus J. Buehler of the Massachusetts Institute of Technology; Robyn Plowright and Carole C. Perry of Nottingham Trent University.
