Tag: de novo protein design

Synthetic Nucleocapsids Have Arrived

Published today in Nature, IPD researchers describe the first synthetic protein assemblies — dubbed synthetic nucleocapsids — that encapsulate their own genome and evolve in complex environments.

Computationally Designed Synthetic Nucleocapsid
Computationally Designed Synthetic Nucleocapsid, Illustration by Institute for Protein Design & Cognition Studio

Synthetic nucleocapsids are built to resemble viral capsids and could be used in future to deliver therapeutics to specific cells and tissues. These icosahedral protein assemblies are based off of previously reported results from the Institute for Protein Design.

The image above visualizes the de novo creation of synthetic nucleocapsids from computationally designed proteins and their evolution to acquire properties that could be useful for drug delivery and other biomedical applications. The narrative was designed as a futuristic hologram projection realized through spiraling DNA composed of binary zeros and ones. The projection and computational imagery evoke futuristic technology and design, while calling out natural evolution through the DNA spiral “time-scale” motif. The heads-up display iconography showing a blood bag, mouse, and RNase A convey the challenges we used to evolve the synthetic nucleocapsids. The single net impression of this image is engaging + enlightening and shows that we are entering the next epoch of synthetic biology in which biological systems can be designed and created from scratch.


The challenges of evolution in a complex biochemical environment, coupling genotype to phenotype and protecting the genetic material, are solved elegantly in biological systems by the encapsulation of nucleic acids. In the simplest examples, viruses use capsids to surround their genomes. Although these naturally occurring systems have been modified to change their tropism and to display proteins or peptides, billions of years of evolution have favoured efficiency at the expense of modularity, making viral capsids difficult to engineer. Synthetic systems composed of non-viral proteins could provide a ‘blank slate’ to evolve desired properties for drug delivery and other biomedical applications, while avoiding the safety risks and engineering challenges associated with viruses. Here we create synthetic nucleocapsids, which are computationally designed icosahedral protein assemblies with positively charged inner surfaces that can package their own full-length mRNA genomes. We explore the ability of these nucleocapsids to evolve virus-like properties by generating diversified populations using Escherichia coli as an expression host. Several generations of evolution resulted in markedly improved genome packaging (more than 133-fold), stability in blood (from less than 3.7% to 71% of packaged RNA protected after 6 hours of treatment), and in vivo circulation time (from less than 5 minutes to approximately 4.5 hours). The resulting synthetic nucleocapsids package one full-length RNA genome for every 11 icosahedral assemblies, similar to the best recombinant adeno-associated virus vectors. Our results show that there are simple evolutionary paths through which protein assemblies can acquire virus-like genome packaging and protection. Considerable effort has been directed at ‘top-down’ modification of viruses to be safe and effective for drug delivery and vaccine applications; the ability to design synthetic nanomaterials computationally and to optimize them through evolution now enables a complementary ‘bottom-up’ approach with considerable advantages in programmability and control.

Read more and obtain a PDF of the paper from the Baker lab web site.  Also read additional news items from Science Daily, GeekWire, UW Newsroom, CEN

The Matrix of Protein Design

The Matrix movie (1999) depicts a future in which the reality perceived by most humans is actually a computer simulated reality called “the Matrix”.  Published today in Sciencethe Baker lab and collaborators report on a new kind of Matrix –  a new reality for large scale computational protein design which can achieve massive data driven improvements in our ability to design highly stable, small proteins from scratch.

Illustration by Gabe Rocklin


Following the White Rabbit, Postdoctoral fellow Dr. Gabe Rocklin led a group of scientists to design and test over 15,000 new mini-proteins (which do not exist in nature) to see whether they form stable folded structures. Even major protein design studies in the past few years have generally examined only 50 to 100 designs.  Synthetic DNA technology and high throughput screening permitted the group to conduct large-scale testing of structural stability of multitudes of computationally designed proteins.  In turn, this allows them to perform a “Global analysis of protein folding using massively parallel design, synthesis and testing“.  

Through iterative improvements in the design process, the group arrived at 2,788 stable mini-protein structures, which is at least 50-fold more proteins than have ever been characterized from natural sources for similar sized proteins.  Their small size and stability may be advantageous for treating diseases when the drug needs to avoid the immune system and reach the inside of a cell.

The publication Abstract is a step into the Matrix as Morpheus explains,

Proteins fold into unique native structures stabilized by thousands of weak interactions that collectively overcome the entropic cost of folding. Though these forces are “encoded” in the thousands of known protein structures, “decoding” them is challenging due to the complexity of natural proteins that have evolved for function, not stability. Here we combine computational protein design, next-generation gene synthesis, and a high-throughput protease susceptibility assay to measure folding and stability for over 15,000 de novo designed miniproteins, 1,000 natural proteins, 10,000 point-mutants, and 30,000 negative control sequences, identifying over 2,500 new stable designed proteins in four basic folds. This scale — three orders of magnitude greater than that of previous studies of design or folding—enabled us to systematically examine how sequence determines folding and stability in uncharted protein space. Iteration between design and experiment increased the design success rate from 6% to 47%, produced stable proteins unlike those found in nature for topologies where design was initially unsuccessful, and revealed subtle contributions to stability as designs became increasingly optimized. Our approach achieves the long-standing goal of a tight feedback cycle between computation and experiment, and promises to transform computational protein design into a data-driven science.

The research has been recognized by opinion leaders and media outlets as a major step for computational protein design.  See articles in Science, Science Daily, Chemistry WorldPhys.orgGEN, and C&E News.



Proteins Made to Order. Researchers at the IPD Design Proteins from Scratch with Predictable Structures

Design of Ideal Folded ProteinsA team from David Baker’s laboratory at the University of Washington in Seattle have described a set of “rules” for the design of proteins from scratch, and have demonstrated the successful design of five new proteins that fold reliably into predicted conformations.  Their work was published Nature.  Learn more at this link.