The team has already used the model to create a new version of cetuximab, a drug commonly used to treat colorectal cancer, that binds to its target with 10 times greater affinity than the original molecule.
The work, which will appear Sept. 23 in an advance publication of Nature Biotechnology, results from a collaboration using both laboratory experiments and computer simulations, between MIT Professors Dane Wittrup and Bruce Tidor.
"New and better methods for improving antibody development represent critical technologies for medicine and biotechnology," says Wittrup, who holds appointments in MIT's Department of Biological Engineering and Department of Chemical Engineering. Tidor holds appointments in Biological Engineering and the Department of Electrical Engineering and Computer Science.
Antibodies, which are part of nature's own defense system against pathogens, are often used for diagnostics and therapeutics. Starting with a specific antibody, the MIT model looks at many possible amino-acid substitutions that could occur in the antibody. It then calculates which substitutions would result in a structure that would form a stronger interaction with the target.
"Combining information about protein (antibody) structure with calculations that address the underlying atomic interactions allows us to make rational choices about which changes should be made to a protein to improve its function," said Shaun Lippow, lead author of the Nature Biotechnology paper.
"Protein modeling can reduce the cost of developing antibody-based drugs," Lippow added, "as well as enable the design of additional protein-based products such as enzymes for the conversion of biomass to fuel." Lippow conducted the research as part of his thesis work in chemical engineering at MIT, and is now a member of the protein engineering group at Codon Devices in Cambridge, Mass.
"Making drugs out of huge, complicated molecules like antibodies is incredibly hard," said Janna Wehrle, who oversees computational biology grants at the National Institute of General Medical Sciences, which partially supported the research. "Dr. Tidor's new computational method can predict which changes in an antibody will make it work better, allowing chemists to focus their efforts on the most promising candidates. This is a perfect example of how modern computing can be harnessed to speed up the development of new drugs."
Traditionally, researchers have developed antibody-based drugs using an evolutionary approach. They remove antibodies from mice and further evolve them in the laboratory, screening for improved efficacy. This can lead to improved binding affinities but the process is time-consuming, and it restricts the control that researchers have over the design of antibodies.
In contrast, the MIT computational approach can quickly calculate a huge number of possible antibody variants and conformations, and predict the molecules' binding affinity for their targets based on the interactions that occur between atoms.
Using the new approach, researchers can predict the effectiveness of mutations that might never arise by natural evolution.
"The work demonstrates that by building on the physics underlying biological molecules, you can engineer improvements in a very precise way," said Tidor.
Expanding on that theme, Wittrup and Tidor also co-teach a class and are writing a textbook focusing on connecting fundamental molecular and cellular events to biological function through the use of mathematical models and computer simulations.
The team also used the model with an anti-lysozyme antibody called D44.1, and they were able to achieve a 140-fold improvement in its binding affinity. The authors expect the model will be useful with other antibodies as well.
The research was funded by the National Science Foundation and the National Institutes of Health.
Written by Anne Trafton, MIT News Office
Elizabeth A. Thomson | MIT News Office
'Living bandages': NUST MISIS scientists develop biocompatible anti-burn nanofibers
16.02.2018 | National University of Science and Technology MISIS
New process allows tailor-made malaria research
16.02.2018 | Eberhard Karls Universität Tübingen
Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale
Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...
For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.
But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...
Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.
The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...
Theoretical physicists propose to use negative interference to control heat flow in quantum devices. Study published in Physical Review Letters
Quantum computer parts are sensitive and need to be cooled to very low temperatures. Their tiny size makes them particularly susceptible to a temperature...
Let’s say the armrest is broken in your vintage car. As things stand, you would need a lot of luck and persistence to find the right spare part. But in the world of Industrie 4.0 and production with batch sizes of one, you can simply scan the armrest and print it out. This is made possible by the first ever 3D scanner capable of working autonomously and in real time. The autonomous scanning system will be on display at the Hannover Messe Preview on February 6 and at the Hannover Messe proper from April 23 to 27, 2018 (Hall 6, Booth A30).
Part of the charm of vintage cars is that they stopped making them long ago, so it is special when you do see one out on the roads. If something breaks or...
15.02.2018 | Event News
13.02.2018 | Event News
12.02.2018 | Event News
16.02.2018 | Information Technology
16.02.2018 | Health and Medicine
16.02.2018 | Physics and Astronomy