Over a year of coronavirus simulations

Like many computational labs, at the start of the pandemic in the US in early 2020, we turned our attention to SARS-CoV-2, aided by a rapidly growing amount of structural data. Since then, as a community, we have learned a tremendous amount about the biophysics of the virus and the proteins it uses to infect and replicate. Our lab in particular has focused on protonation states of the main protease (Mpro), the closed-to-open transition of the spike protein, and its binding to the receptor ACE2 (see our coronavirus page for more). The last year and a half have also demonstrated a tremendous degree of communication and cooperation amongst the scientific community and especially the computational chemistry community, including in two ACS symposia at the spring meeting (“A Call to Action: The Many Roles of Computational Chemistry in Addressing COVID-19” organized by JC Gumbart and Rommie Amaro) and the fall meeting (“Computational Chemistry of COVID-19: Lessons Learned and Future Directions” organized by Katarzyna Świderek and Carlos Simmerling). What discoveries will the next year and a half bring?

A bacterial weapon

Bacteria are often in battle with each other, fighting over limited resources. One of the weapons they bring into battle is a toxin delivery system known as Contact-Dependent growth Inhibition (CDI). Composed of two proteins, a toxin called CdiA is delivered via a transporter in the bacterial outer membrane called CdiB. In collaboration with structural biologists at NIH, Zijian, Karl, and JC determined how CdiB can be primed for subsequent delivery in a recent paper in eLife. They calculated the energy required to extract the helix that plugs CdiB in its resting state, finding it to be relatively modest. This energy could be provided, for example, by the binding of CdiA prior to its export.

Simbac at Biophysics 2020

David, Anna, Katie, Jinchan, Atanu, and JC stand in front of the Gaslamp Quarter (Andrew is not pictured here).

The group just finished a successful trip to the 2020 Biophysical Society meeting in San Diego! David presented a poster on autotransporters; Anna gave a talk on HBV; Katie, Andrew, and Jinchan presented posters on BamA and the BAM complex; Atanu presented a poster on Aβ; and JC gave a talk on the multidrug efflux pump AcrAB-TolC. Next, it’s on to Boston for BPS 2021!

Molecule of the month


Every month, the Protein Data Bank highlights a specific molecule with a focus on its structure and its function. For the month of September, they are highlighting nanodiscs, which are tiny discs of lipids surrounded by two belt-like proteins. Originally engineered from high-density lipoproteins that mop up cholesterol in the blood, nanodiscs are most often used to study membrane proteins, which can fit inside, one per disc typically. Although widely used, the nanodisc structure is rarely seen. One of the first high-resolution images came from our 2011 paper on visualizing membrane-protein insertion through SecYE, embedded in a nanodisc, during translation by the ribosome, using cryo-electron microscopy and molecular dynamics simulations (see the image at right). Thanks to RCSB for bringing attention to this structure!

Simulations and disease

In most cases of disease, the cause is a complex interplay of various sources, including both genetic and environmental. But in some cases, the cause can be traced to a single mutation in a single gene. In two recent studies, molecular dynamics simulations contributed to our understanding of the function of the specific protein responsible for a particular disease. In the first study, simulations elucidated aspects of the signaling pathway in CFTR, a chloride channel that, when mutated, leads to the disease cystic fibrosis (study). In the second study, simulators teamed up with medical doctors to understand how a mutation to an IL2 receptor protein (pictured) may have led to severe immunological problems in a patient (study and news article). These two examples hopefully point the way towards bringing MD simulations closer to the bedside.