Stephen Grill presenting his data
On Monday, June 10, the annual Engineering and Physical Biology Symposium took place in the Northwest Building. Researchers and students from the EPB core (MCB, Physics and SEAS) as well as from other Harvard departments, HMS and MIT, more than 50 in all, gathered to attend a series of talks addressing fascinating questions in the fields of protein folding, DNA knotting in viruses, dynamics of the actomyosin cytoskeleton, and DNA homology search. An afternoon session of graduate student presentations was also held for the EPB core.
Even though addressing very diverse topics, a common theme specific to research in physical biology emerged from the public session: the search of models simple enough to be tractable but detailed enough to capture essential features of the system.
This was perfectly exemplified by the first speaker, Jeremy England from MIT, who presented his elegant solution to the problem of protein folding and deformation. By neglecting atomistic details and only using a few ingredients such as the connectivity and hydrophobicity of amino acids combined to a very simple constraint on protein volume (to avoid crumpled, unrealistic conformations), he discovered a new way to perceive protein conformation as the combination of a set of “ideal” conformations. That combination can change upon interaction with ligands for example, explaining in addition the large-scale protein rearrangement known as allostery. Hence the few carefully chosen parameters lead to a computationally efficient model with a strong predictive power.
The next speaker, in contrast, showed us how tiny details can sometimes have a decisive impact on a model. Christian Micheletti from SISSA in Trieste, Italy, used a coarse-grained model of DNA to explain how DNA becomes knotted inside viral capsids where it is tightly packed. This packing is not fully random, as the DNA creates spools on the inside surface of the virus to minimize bending energy. Models including only DNA rigidity as a parameter always failed to reproduce the knotting state of DNA inside viruses. Until, that is, Micheletti and colleagues noticed that since DNA is so tightly packed, it interacts strongly with itself and, because of its helical nature, prefers to align with itself with a slight tilt. When adding that simple ingredient into his simulation, Micheletti could finally reproduce the experimental knot distribution, solving a puzzle that had been waiting for years.
Stephan Grill from the Max Planck Institute in Dresden, took us then to the complex system of the actomysin network, the active gel of actin filaments and myosin motors that plays an important role in cell mechanics in particular during embryonic development. For example, in zebrafish during epiboly (the growth of an outer layer of cells about a slower-growing inner layer) a contractile actomyosin ring drives the envelopment process of the yolk by a layer of cells. By using in vivo laser cutting of the actomyosin ring along different directions, Stephan Grill and colleagues showed that circumferential contraction of the ring is not the sole driving force as previously believed. Measuring flow of actin and myosin, they realized that a driving force could be friction between that flow and the underlying substrate. They developed that idea into a careful physical model abstracting away molecular details, and confirmed that this mechanism, close to the one driving cell crawling, was the major force driving epiboly. Hence Grill showed that even such a complex problem involving molecular as well as cell dynamics is amenable to a rational simplified model.
Finally, Mara Prentiss from Harvard University, showed us how to feed detailed molecular structure information into a simplified model for a complex process. When DNA in a cell has to be repaired, a stretch of it is converted into single-stranded DNA that then searches for its complementary strand on another chromosome where it replaces the original strand. The task for that single-strand to find its exact matching sequence within the entire genome, even of a small organism like E.coli, is daunting, and requires a right balance between speed (the cell cannot wait hours) and accuracy (exactly the right sequence has to be found). The protein RecA plays the essential role in that process by binding to both single- and double-stranded DNA and putting them under mechanical tension. By plugging the relevant energies involved in protein-DNA interactions and DNA stretching into a simplified sequential search for homology, Mara Prentiss showed that the entire search proceeds a low energy level close to thermal energy ensuring that mismatches will be detected. Additionally, her model reveals the existence of check-points where interaction between homologous regions is stabilized. Taken together, Mara Prentiss’ model proposes for the first time a solution to homology search respecting speed and accurary.
That these physical models could address biological questions adroitly was an enouragement to the developing field of physical biology that EPB has been dedicated to furthering.