There’s a hitch in the swing of a protein that delivers the flu virus.

In a paper in the Proceedings of the National Academy of Sciences, the Rice-Baylor team led by biophysicist José Onuchic and biochemists Jianpeng Ma and Qinghua Wang delves further into a glycoprotein complex it began to define in a 2014 paper.

That protein, hemagglutinin, sits on the surface of flu viruses and helps them attach to and transport through the protective membranes of target cells.

The paper begins to define the mechanism that allows the protein to unfold and refold in a snap, changing its form to expose a peptide that attaches the virus to a cell and begins infection. The researchers believe therapeutic drugs can use this mechanism to shut the virus down, Phys reported.

“This protein starts in a folded state and goes through a global transformation, refolding in a completely different state,” said Onuchic, co-director of Rice’s Center for Theoretical Biological Physics (CTBP). “But there’s a small part in the center that evolution has conserved.”

That single conserved amino acid residue is the hitch that makes the protein pause in the process of refolding. It allows a fusion peptide buried inside to bind to the target cell and begin infecting it. Without the pause, the refolding would be too quick for binding to take place. Lead author and Rice postdoctoral researcher Xingcheng Lin modeled that part of the protein, the B-loop of the HA2 domain. HA2 sits beneath another domain, a cap known as HA1 that mutates to escape past defenses. Lin explained that HA1 is a common target for flu medications because the exposed cap domain is more accessible than the protected HA2 domain.

The problem is that HA1 mutates constantly to resist drugs, he said. That influences how effective flu vaccines are every year. Lin and Onuchic said HA2 presents a better target for drugs because the mechanism is highly conserved by evolution.

“If a drug targets HA2, the domain cannot escape by making mutations because the mutations themselves would make it nonfunctional,” Lin said. “That kind of drug could become a universal vaccine.”

HA2 is a trimeric structure that, when triggered by acidic conditions in the environment near a target cell, transforms itself from a random loop to a coiled coil. Even with the pause, it unfolds and refolds in a fraction of a second, far too fast for microscopes to see. But a computer simulation of the process can be slowed down.

That happens to be a specialty of the CTBP, which uses programs that analyze the energy landscape of proteins to predict how they will fold. Onuchic and his colleagues are pioneers in the theory that folding proteins follow an orderly, “funneled” process that depends on the intrinsic energy of every atom in the chain, each of which constantly seeks its lowest energy state. If all the atomic “beads” can be identified, it’s possible to simulate the complex folding process.

The Rice researchers often use coarse-grained models of proteins, a subset of atoms that represent the whole, to predict how they will fold. The new study was much more ambitious and set out to predict the complex unfolding and refolding by using not only every atom in the chain but also every atom in its liquid environment, Onuchic said. Lin modeled 40 microseconds (millionths of a second) of the HA2 domain transition that represents the entire process, which takes 1.4 milliseconds (thousandths of a second) to complete. Even that shortened process took two years of computer time to deliver results, he said.

“The simulated domain is about 3,000 atoms, but when the environment, including water, is accounted for, the total simulation incorporates around 100,000 atoms,” Onuchic said. “It’s still an enormous simulation that required state-of-the-art techniques.”

Previous theories based on crystallographic images of the before-and-after proteins put forth the idea of a spring-loaded domain that appeared to attach to the target cell after the cap’s removal. Onuchic said the complete model of HA2 supports a different mechanism.

“We figured out there’s a bunch of energy that makes the final state of HA2 much more stable than the initial state,” he said. “But with the spring-loaded mechanism, most of the energy would already be wasted by the time it forms the coiled coil and binds the cell and viral membranes. It wouldn’t leave any energy to pull the membranes together.

“That’s why we decided to do a full calculation of the system – all the atoms of the protein and all the water,” Onuchic said. “It was a gigantic effort.”

The conserved hydrophilic (water-attracting) residue, known as Thr59, is of particular interest to the researchers not only for the way it disrupts folding and allows the virus to attack, but also because it has a twin.

“In the full evolutionary tree, these viruses fall into two groups, and the difference appears to be this residue,” Onuchic said. “They split 1,500 years ago and somehow, after this separation, they’re fully conserved. They haven’t been able to change that residue no matter what, and we believe that makes this residue important.”

The current research focused on the group that incorporates Thr59 and causes the H3N2 strain responsible for the Hong Kong flu, Lin said. The other residue, Met59, appears in the H1N1 strain that caused the Spanish flu.

“We still have a long way to go to understand the entire protein,” he said. “Here, we only studied one domain of one protein, and there are several others that are very important to its function.”

“But what Xingcheng has already done is a computational tour de force,” Onuchic added. “He showed how this particular residue breaks the helical symmetry of the domain and makes it unstable enough to give the peptide time to grab the membranes.”

“We are going into winter season. There is no such thing [stopping the operations],” Erdogan said in Justice and Development (AK) party’s parliamentary group meeting.

“The operation is continuing. We will not stop. We will push them. Nobody should feel offended,” the Turkish president added, Anadolu Agency reported.

His remarks came several days after seven soldiers and two village guards were killed in fighting with PKK terrorists in the southeastern province of Hakkari.

Meanwhile, the Interior Ministry announced on Tuesday that at least 46 PKK terrorists have been killed in military operations in eastern Turkey.

Erdogan reminded that commanders of Turkish army are reviewing the military troops present along the Turkey’s southeastern borders.

He said PKK is a tool of foreign powers to disrupt peace in the region, while Daesh (also known as ISIL or ISIS) is a bloody terrorist organization irrelevant to Islam.

The PKK — listed as a terrorist organization by Turkey, the US and the EU — resumed its armed campaign against Turkey in July 2015.

Since then, it has been responsible for the deaths of more than 1,200 Turkish security personnel and civilians, including a number of women and children.

Led by Professor Alfonso Jaramillo in the School of Life Sciences, new research has discovered that a common molecule — ribonucleic acid (RNA), which is produced abundantly by humans, plants and animals — can be genetically engineered to allow scientists to program the actions of a cell.

As well as fighting disease and injury in humans, scientists could harness this technique to control plant cells and reverse environmental and agricultural issues, making plants more resilient to disease and pests.

RNAs carry information between protein and DNA in cells, and Professor Jaramillo has proved that these molecules can be produced and organised into tailor-made sequences of commands — similar to codes for computer software — which feed specific instructions into cells, programming them to do what we want.

Much like a classic Turing computer system, cells have the capacity to process and respond to instructions and codes inputted into their main system, argues Professor Jaramillo.

Similar to software running on a computer, or apps on a mobile device, many different RNA sequences could be created to empower cells with a ‘Virtual Machine’, able to interpret a universal RNA language, and to perform specific actions to address different diseases or problems.

This will allow a novel type of personalised and efficient healthcare, allowing us to ‘download’ a sequence of actions into cells, instructing them to execute complex decisions encoded in the RNA.

The researchers made their invention by first modelling all possible RNA sequence interactions on a computer, and then constructing the DNA encoding the optimal RNA designs, to be validated on bacteria cells in the laboratory.

After inducing the bacterial cells to produce the genetically engineered RNA sequences, the researchers observed that they had altered the gene expression of the cells according to the RNA program — demonstrating that cells can be programmed with pre-defined RNA commands, in the manner of a computer’s microprocessor.

Professor Alfonso Jaramillo, who is part of the Warwick Integrative Synthetic Biology Centre, commented:

“The capabilities of RNA molecules to interact in a predictable manner, and with alternative conformations, has allowed us to engineer networks of molecular switches that could be made to process arbitrary orders encoded in RNA.

“Throughout the last year, my group has been developing methodologies to enable RNA sensing the environment, perform arithmetic computations and control gene expression without relying on proteins, which makes the system universal across all living kingdoms.

“The cells could read the RNA ‘software’ to perform the encoded tasks, which could make the cells detect abnormal states, infections, or trigger developmental programs.”