Researchers create first custom designed protein crystal - Dimmable LED Light Bulbs Manufacturer

Lanci and graduate studentChristopher M. MacDermaid, all of the Department of Chemistry inPenn's School of Arts and Sciences. Also contributing to the workwere Seung-gu Kang and Xi Yang, formerly of the chemistrydepartment, and Rudresh Acharya, Benjamin North, X. Jade Qiu andWilliam F. DeGrado, formerly of Penn's Perelman School ofMedicine's Department of Biochemistry and Biophysics.

The team's research was published in the Proceedings of the National Academy of Sciences ( "Computational design of a protein crystal" ). An illustration of the researchers' target protein crystal. (Art:Christopher MacDermaid) Proteins are folded strings of molecular building blocks known asamino acids; their different functions are determined by theirsequences of amino acids and the shapes they take when folded. Asproteins are involved in most biological processes, determiningsequences and structures is crucial to many scientificundertakings, such as understanding disease mechanisms or designingdrugs to disrupt them.

To determine protein structures, scientists use crystals, whichconsist of many copies of a single protein lined up and stackedtogether. By irradiating the crystal with powerful X-rays, they canmeasure the way the light diffracts off the atoms and piecetogether the protein's overall three-dimensional shape andcomposition. Most proteins don't naturally crystalize, however, andmaking crystals of sufficient quality to do diffraction studies isa hit-or-miss process that can take years of painstaking work. Protein crystals are also attractive as a nano-scale buildingmaterial, as their properties, particularly their exteriorsurfaces, are highly customizable.

However, bioengineers run intothe same hurdles as crystallographers; making a protein crystalwith a particular structure is a complex, hard-to-predict task. "People have designed crystals out of smaller, much less complexmolecules than proteins, but protein design is much more subtle,"Saven said. "It's a complicated symphony of intermolecularinteractions." As accounting for these many interactions is one of the principalchallenges behind designing a protein crystal, the researchersselected a complicated, honeycomb-shaped target to show theirprocess could be widely applied. That process involved finding the right protein and designing howcopies of it will interact with each other.

To tackle thetremendous number of variables involved, the researchers developeda theoretical method and computer algorithm to search throughpotential proteins for ones that could crystalize into theirtarget. The researchers targeted a crystal built using a relatively smallprotein containing a sequence of 26 amino acid positions. Theresearchers assigned specific amino acids to eight of thepositions, but, with 18 different types of amino acid to choosefrom for each of the remaining 18 slots, the algorithm addressedwell more than 1022 potential combinations. On top of that, theresearchers had to account for other characteristics, such as thespacing between proteins and their orientation with respect to oneanother.

These variables multiplied the already astronomicallylarge number of possibilities, so maximizing the efficiency of thesearch was a priority. "We worked on synthesizing both of those steps, doing thecharacterization of structure and the sequence at the same time,"Saven said. "As we move through this process, we eliminate thingsthat will never work, such as proteins where atoms overlap in spaceor where amino acids don't fit into a given site. At the same time,we identify proteins that, as you vary the structure, are likely toyield a crystal." "Combining theory with recent advances in computer hardware havereally allowed us to consider thousands of candidates, instead of ajust a handful," MacDermaid said After a full day of computation, the researchers' algorithmproduced a handful of promising candidates. Critically, theseproteins had very different sequences from one another.

Even withtheir computational approach, finding the protein that wouldcrystalize into their target involved trial and error. "One reason to consider a very broad range of candidate proteins isthat in nature you have proteins that are the same across organisms-- the same name, structure and function -- but their sequences areoften very different," Saven said. "Nature finds many differentpossible solutions to the same problem, so we wanted to developmethods that allow us to say something about many disparatepossible solutions." This approach is particularly important when considering theeventual applications of a protein crystal. One sequence maycrystalize perfectly but be toxic to cells, making it difficult toproduce or unusable for a biotechnological application. A non-toxicsequence may form the crystal but only in tiny quantities.

"It's an important part of our algorithm that you don't end up withsingle sequence and put all of your eggs in one basket," Lancisaid. "You get a large landscape of possibilities, improving theodds that you'll find one that can overcome all the experimentalchallenges you can't control for." Beyond presenting multiple candidates, the computational approachhas the advantage of finding proteins that will producediffraction-quality crystals. The researchers saw their candidateproteins begin to crystalize within hours, a process that can oftentake weeks or months. Though they achieved their goal, the target crystal the researchersproduced is just a proof of concept.

The researchers' algorithmrepresents an important tool kit for better understanding theprinciples behind protein crystallization and the many variablesinvolved. By adding that understanding back into the algorithm,researchers will be able to search for candidate proteins moreefficiently. "There's still much we don't know about the interactions thatgovern crystallization," Saven said. "With this technique, we canexplore what those interactions are or how we might take anexisting protein and engineer those interactions so we get muchbetter structures.".

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