Molecule of the Month in Virtual Reality (Dec 2018)
We’re starting a new series here at Nanome following the lead of RCSB’s Molecule of the Month. RCSB (Research Collaboratory for Structural Bioinformatics) publishes this series through their educational portal, PDB-101, which offers free access to an incredible range of educational resources that enable visitors to build up their foundations in structural biology. In our spin on this molecule of the month series we expand on the subject in PDB-101 to dig deeper into the connection between the future of protein engineering and Virtual Reality.
This month, the spotlight is on a technique used for developing proteins with specialized functions, which was recognized by the 2018 Nobel Prize in Chemistry — Directed Evolution. This technique originated in the 1960s and imitates natural selection in a process that drives the evolution of a protein towards the desired structure and function of the user. Dr. Frances Arnold pioneered the use of this technique in developing enzymes with new functions and tolerances to industrial production conditions. She received the 2018 Nobel Prize in Chemistry for her work.
Where does Nanome come into the picture? The RCSB article has several excellent graphics, but Nanome is augmenting the experience for readers that want to dig further into the original research papers describing these proteins. The specifics are laid out in detail in the research papers and we believe that the reader’s ability to absorb these technical details could be greatly improved by an enhanced visualization environment. Nanome provides intuitive physical context to support the reader’s understanding of the hard scientific details in a way that’s difficult to reproduce through mediums other than VR.
One of the molecules highlighted this month is 5UCW, which was engineered to perform a reaction not found in any natural enzymes, and could previously only be performed with the use of heavy metal catalysts. The paper on 5UCW states in the abstract that although iron complexes are generally poor catalysts for C-H amination (the chemical reaction that this protein has been engineered to perform), this enzyme’s protein framework enables the otherwise inactive iron atom within the protein to catalyze this reaction. As a reader, I have an immediate desire for a visualization to supplement this description with some visual intuition.
In Figure 4.b in the paper, some of the key residues involved in creating the catalytically favorable protein structure are shown to illustrate their roles in catalysis — notably, it describes how the S400 residue ligates the iron responsible for catalyzing the C-H amination. Investigating this region of the protein in Nanome makes the spatial relationship between the ligating S400 residue and the iron center of the heme ligand immediately obvious.
The Arnold lab also engineered a protein found in nature (4kqw) which uses an NADPH cofactor instead of NADH (4kqx) which is a more readily available cofactor in the environment of interest. This enabled them to optimize an important cellular reaction pathway. Side by side comparison in Nanome of the original enzyme with the engineered one provides an intuitive way to understand the key changes made to enable this optimized reaction pathway.
We hope this inspires you to open up Nanome and take a look at these proteins for yourself! Open the Load Structure menu and import from RCSB Database the following PDB Codes: 5ucw, 3wwj, 6am8, 1wdw, 4kqw, 4kqx
