MFBM Subgroup Contributed Talks

Wayne Hayes

UC Irvine

"The One True Way to use GO terms to evaluate Network Alignments"

Sequence alignment has contributed immensely to our understanding of biology, evolution, and disease. While the genome encodes recipes for making proteins, the function of many proteins remains elusive. Since the function of a protein is intimately tied to its interaction partners, the topology of protein-protein interaction (PPI) networks holds promise as way to decode function. Topologically-driven network alignment attempts to find the best mapping between the PPI networks of two species by finding the greatest amount of common network topology. However, network alignment research is still in its infancy and there are dozens of proposed methods but no objective, mathematically rigorous methods to compare their results. Here we propose a rigorous, formal method to compute the p-values of shared GO terms between pairs of proteins found by a network alignment, compared to random alignments. We compare our p-values to billions of actual random alignments to demonstrate that the p-values are correct within statistical uncertainty of the sample random alignments.

Giulia Palermo

UCR

"Harnessing graph theory to decrypt the allosteric mecahnism in CRISPR-Cas9"

CRISPR-Cas9 is a bacterial adaptive immune system that emerged as the centerpiece of a transformative genome editing technology. In this system, an intriguing allosteric communication has been suggested to control the DNA cleavage activity through the flexibility of the catalytic HNH domain. Here, we report about the use of molecular dynamics and graph theory-based analysis methods to describe the structural and dynamic determinants of the allosteric signaling in the CRISPR-Cas9 complex. Network models derived from graph theory reveal the existence of a contiguous dynamic pathway that enables the information transfer across the HNH domain. This pathway spans HNH from the region interfacing the RuvC nuclease and propagates up to the DNA recognition lobe in the full-length CRISPR-Cas9, such transferring the signal of DNA binding at the nuclease domains for concerted cleavages of the two DNA strands. These findings reveal the mechanism of signal transduction within the CRISPR-Cas9 nuclease and pose the basis for the complete mapping of the allosteric pathway, and of its role in the DNA on-target specificity, helping engineering efforts aimed at improving the genome editing capability of CRISPR-Cas9.

Dennis Manjaly Joshy

UC Santa Barbara

"A Koopman Operator Approach for Genetic Circuit Design"

We consider the problem of genetic circuit design to achieve an arbitrary data-driven or function-based performance specification. We review the open nature of this nonlinear design problem and its relation to the optimal and robust controller synthesis problem. We show how a class of biological networks, modeled with first order, zeroth order, and Hill function dynamics can be represented with a Koopman operator to yield a linear representation of system dynamics on a space of functions. This formulation allows us to directly solve the controller synthesis problem to meet a given performance specification as an optimization problem on a particular physical basis of observable functions. We demonstrate our approach on the optimization of a positive amplifier circuit in bacteria, showing how design recommendations from our controller synthesis algorithm can be translated to DNA sequence-level specification. These results solve an outstanding problem in genetic circuit design - synthesis of closed-loop systems to meet a target performance specification.

Ying Zhang

Brandeis University

"Immersed Boundary Simulations of Red Blood Cells Near Vessel Walls"

Platelets constitute an essential component of human blood due to their role in the formation of hemostatic plug and thrombus. The occurrence of these biological phenomena requires platelets stay within close proximity to the vessel walls, initiating platelet-wall interaction. It has been understood that the red blood cells (RBCs) play an important role in platelet near-wall excess. Healthy RBCs are highly deformable objects, and thus can acquire lift forces from vessel walls from their deformation to propel them away from the wall, a phenomenon known as wall-induced migration. Migration of RBCs away from the wall leads to the formation of a cell-depleted layer near the wall, which has a large effect on the motion of platelets. Here we use the immersed boundary method to investigate the influence of cell stiffness and shape on the wall-induced migration. In particular, we focus on analyzing how lift force and mobility change over time when a RBC is placed close to the wall. Our preliminary results suggest that deformation of a RBC leads to a larger lift force when the RBC is closer to the wall, increasing the likelihood of RBCs migrating away from the vessel wall.