A new physical model of peptide and protein folding has been published in PNAS highlighting innovative work from graduate student researcher Promita Chakraborty and LBNL senior scientist and Molecular Foundry Biological Nanostructures Facility Director Dr. Ron Zuckermann. This recent work advances an elegant strategy to design, construct, and test a novel scaled model of polypeptide chains, dubbed Peppytides.
Peppytides are an original tactile interface to the complicated world of protein folding. They boast dynamic, flexible chains that can fold into secondary and tertiary structures while retaining the key biophysical parameters of the parent proteins and peptides. Although these models are highly intuitive and understandable, they preserve the inherent complexity of the twists, turns, and folds that underlie protein folding. Peppytides are not the stuff your sophomore year biochemistry model set was made out of. Rather, these models represent the cutting edge of kinesthetic molecular visualization for molecules with a large number of atoms. They can be equally as useful and accessible in a classroom as in a research laboratory.
The Peppytide strategy employs remarkable care in the design of each element in order to ensure that the model is accurate in conveying all the relevant parameters of protein folding and chain interactions. Via clever and innovative design, critical constraints are introduced to allow a Peppytide to fold into all existing secondary structures possible in its biological counterpart. Magnetized bonds precisely positioned ensure the reproduction of torsion angles and long-range H-bonding interactions. A 3D printer is used for high-throughput production of ultralight building blocks highlighting a peptide bond and alpha-carbon disconnection approach that includes adaptors for installation of all mechanical components. The approach also includes adaptors for installation of all mechanical components.
The end product isn’t just beautiful; it’s also highly functional. Because of its accuracy, playing with a Peppytide model offers a unique opportunity to explore the topology of a Ramachandran plot with your own hands! If this movie of building block 3D printing isn’t futuristic enough for you, check out the awesome gallery of the researchers putting the Peppytide assembly process into action at the bottom of this page. For tinkerers and learners of any age, it’s hard to restrain from wanting to touch or build up these molecular legos yourself.
In fact, one of the major goals of the project was to make the model as open-source as possible with information on assembly freely available online. Remarkably, all building materials can be easily found at a local hardware store. Looking forward to the future, the next steps for Peppytides reaching the public is very bright, especially towards positively impacting classrooms, lectures, and exhibits at the Lawrence Hall of Science for example. While holding the model in your hands, it’s easy to see how impactful it can be to kinesthetically interact with challenging concepts in biomolecular interactions.
In many ways, the elegance of the Peppytides and the ease of model assembly conceal the challenges behind the research effort. Peppytides are the successful outcome of a two-year effort to expand scientific frontiers. Developing a dynamical physical model of a peptide is a truly novel concept and it does brush up against the status quo of relying on a computer screen as the primary mode of molecular visualization. Promita recalls that at the early stages of project development, “people couldn’t imagine how a [physical] model that could fold could work […] since a computer can do it so easily.” The scientific achievement of the Peppytide model has greatly expanded the limits of computer generated models and has altered pre-conceptions. It is rewarding that there is now a burgeoning excitement for this innovative approach. Chakraborty and Zuckermann’ssuccessful collaboration is representative of the strong and vibrant scientific community at the Molecular Foundry of Lawrence Berkeley National Lab.
From a research perspective, the hope is that the first Peppytides will be a scientific launchpad for further model improvements, developments, and discovery. Next steps are underway to grow and expand on the model. Chakraborty and Zuckermann plan to explore building “squishier” peptides, installing different arrays of amino acid side chains, and interfacing the physical model with computer feedback and response. Physical interactivity with computer databases is a particularlypromising area for the development of new protein structures and the exploration of novel protein folding pathways. With the success of efforts such as Fold-It, a Peppytide linked protein modeling system could be revolutionary on many different fronts: addressing protein folding questions,assisting with basic science education, and significantly reducing computational time (in molecular modeling. Beyond the confines of biological world, Peppytides offer promise for collaboration with the robotics community for accessing exciting questions in the broader field of self-assembly.Peppytides constitute a true scientific breakthrough. As Dr. Zuckermann explains, “we were successful in making something that was intuitive, understandable and complex […] this jumps out of the box”.