Design of a Photoswitchable Cadherin

There is a growing interest in engineering proteins whose function can be controlled with the spatial and temporal precision of light. Here, we present a novel example of a functional light-triggered switch in the Ca-dependent cell–cell adhesion protein E-cadherin, created using a mechanism-based design strategy. We report an 18-fold change in apparent Ca²⁺ binding affinity upon illumination. Our results include a detailed examination of functional switching via linked changes in Ca²⁺ binding and cadherin dimerization. This design opens avenues toward controllable tools that could be applied to many long-standing questions about cadherin’s biological function in cell–cell adhesion and downstream signaling

Modelling Ethical Algorithms in Autonomous Vehicles Using Crash Data

In this paper we provide a proof of principle of a new method for addressing the ethics of autonomous vehicles (AVs), the Data-Theories Method, in which vehicle crash data is combined with philosophical ethical theory to provide a guide to action for AV algorithm design. We use this method to model three scenarios in which an AV is exposed to risk on the road, and determine possible actions for the AV. We then examine how different philosophical perspectives on agent partiality, or the degree to which one can act in one's own self-interest, might address each scenario. This method shows why modelling the ethics of AVs using data is essential. First, AVs may sometimes have options that human drivers do not, and designing AVs to mimic the most ethical human driver would not ensure that they do the right thing. Second, while ethical theories can often disagree about what should be done, disagreement can be reduced and compromises found with a more complete understanding of the AV's choices and their consequences. Finally, framing problems around thought experiments may elicit preferences that are divergent with what individuals might prefer once they are provided with information about the real risks for a scenario. Our method provides a principled and empirical approach to productively address these problems and offers guidance on AV algorithm design

Computational design of a modular protein sense-response system.

Sensing and responding to signals is a fundamental ability of living systems, but despite substantial progress in the computational design of new protein structures, there is no general approach for engineering arbitrary new protein sensors. Here, we describe a generalizable computational strategy for designing sensor-actuator proteins by building binding sites de novo into heterodimeric protein-protein interfaces and coupling ligand sensing to modular actuation through split reporters. Using this approach, we designed protein sensors that respond to farnesyl pyrophosphate, a metabolic intermediate in the production of valuable compounds. The sensors are functional in vitro and in cells, and the crystal structure of the engineered binding site closely matches the design model. Our computational design strategy opens broad avenues to link biological outputs to new signals

Design of a Photoswitchable Cadherin

[Image: see text] There is a growing interest in engineering proteins whose function can be controlled with the spatial and temporal precision of light. Here, we present a novel example of a functional light-triggered switch in the Ca-dependent cell–cell adhesion protein E-cadherin, created using a mechanism-based design strategy. We report an 18-fold change in apparent Ca(2+) binding affinity upon illumination. Our results include a detailed examination of functional switching via linked changes in Ca(2+) binding and cadherin dimerization. This design opens avenues toward controllable tools that could be applied to many long-standing questions about cadherin’s biological function in cell–cell adhesion and downstream signaling