P like Parasites – or of structures and staircases
“This staircase did a lot for me.” Prajwal Nandekar still remembers the spiral staircase in the HITS building leading down to the coffee bar years after he left the institute. “Once, when I was really stuck in my work, its structure put me on the right track.”
To make the story behind this cryptic remark a bit clearer, you have to know that Nandekar is a pharmaceutical scientist and specialist in computer-aided drug discovery and that structures – usually those of proteins – are the linchpin of his daily research. From 2015 to 2019 he worked as a Postdoctoral researcher in Rebecca Wade’s Molecular and Cellular Modeling group at HITS on actin, a protein that is important for the structure and movement of all our cells. The problem – or the advantage, depending which side you are on – with actin is that it has differences in sequence, and therefore structure, in parasites, for example malaria, and human cells. With dire consequences for the latter.
Which brings us straight to the grim topic of this post. According to the World Health Organization (WHO), malaria, which is spread by mosquitos, still kills almost half a million people each year with children below the age of five being the most vulnerable group. So far, all efforts to wipe this persistent disease off the planet have been in vain. The most promising strategy is a combination of insecticides to keep the numbers of mosquitos down, and medical therapies.
And that is where Nandekar and his project come in, since many medical therapies rely on the human immune system. Unfortunately, when it comes to beating malaria parasites, our immune cells are just not fast enough to catch the intruder. Together with his advisor Rebecca Wade and his colleagues Kashif Sadiq (HITS), Freddy Frischknecht, Ross Douglas and Hirdesh Kumar (Heidelberg University Hospital) and with the support of a Heidelberg University FRONTIER program grant, Nandekar took a closer look at the reason for this and set out to identify what lies behind the faster movement of the malaria-causing parasite in humans. Which meant to take a closer look at the omnipresent actin.
As already mentioned at the beginning of this post, actin is a protein that participates in many important cellular processes, including our immune system, where it enables the cells to move and capture invading pathogens. To achieve this, many actin proteins assemble together to form rope-like structures called filaments. But these filaments also make the cells of the malaria parasite move – up to ten times faster than our own immune cells. So where is the difference? And what makes the parasite so much faster? The team assumed that the reason must lie in the sequence of the protein itself and Nandekar’s colleagues at the University Hospital started to replace parts of the parasite protein with corresponding sections of protein from mammalian actin in the lab, which produced the desired effect: the parasites that survived became significantly slower.
“The parasite moves faster because their actin protein structures are having a faster assembly rate and a shorter length than the human protein,” says Prajwal. “But if we want to get to the bottom of this biological problem, then we need to look at the details. With the help of High Performance Computing and molecular modeling software, the analysis of structure in atomic detail gives you an in-depth understanding of what is exactly happening during the biological process.”
The use of computational simulations and multiscale modeling of biomacromolecular structures has revolutionized the research on biological and chemical processes. Fortunately, Nandekar had access to the necessary high-performance computers (HPC) at HITS to automate the process of calculations by writing programs and scripts, that helped him to reduce the time required to develop several models, some of them at atomic detail. Nevertheless, a major challenge in this project was the large number of atoms in actin filaments and so, to make the study computationally feasible, the scientists had to model the actin filaments with a so-called coarse-grained model. These models are used for simulating biomolecular processes by using a simplified representation. But still the project had its ups and downs. For one thing, he relied on data in public databases like all theoretical scientists to simulate how the structure and dynamics of actin filaments change when individual sections are replaced. And it was just one tiny error in one of these databases, a single discrepancy in these data – a single amino-acid residue, to be exact – which almost brought the project to an end after only six months and Nandekar had to start again from scratch by remodeling everything. For another, he also needed some inspiration to analyze the structure of the protein and that is where the HITS staircase comes in:
“It was on a very good day, while I was having coffee with my colleagues Stefan, Daria, Goutam and Kashif in the coffee bar, that I suddenly realized that the actin structure could somehow look like the architecture of the staircase. That moment was really epic for me.”
The findings of Nandekar and his colleagues have since helped other scientists around the world to look for chemical compounds that target the actin filaments of the malaria parasite and affect either their building or breakdown. For Nandekar, working on this project was a life-time experience, not least because the staircase in the HITS coffee bar put him back on track when he needed it most – which is just another proof that structure is to be found everywhere.
More information on this research is to be found here: