Swann, S. | Search bioRxiv

bioRxiv2024

Calculating Muscular Driven Speed Estimates for Tyrannosaurus

Top speed estimates of extinct dinosaurs have been of long-standing interest to gain better understanding of the animals lifestyle and ecology. Tyrannosaurus rex top speeds have been examined using a wide range of methods that draw on more traditional biomechanical formulas, computer simulations, and allometric equations based on mass. However, these calculations may be made more precise using input from contemporary research on anatomy and biomechanics that account for mass allometry and scaling. This study builds on existing studies in anatomy, biomechanical data, and established equations for locomotion to calculate a muscular driven range of top speed for several (n=4) specimens that had sufficient data to undertake this work. When properly refined with additional data on muscle mass allometry and scaling, several adult specimens of T. rex could confidently be placed in a range of top speed from 7.7 to 10.5 m/s, and possibly up to 10.7 m/s. Additionally, a younger specimen of T. rex was analyzed and found to have a higher top speed than the adult T. rex at 6.3 to 14.5 m/s. Although the estimated top speeds in this study are slower than some previous estimates, these results find some support for slow running gaits and reinforce interpretations of T. rex as an active and effective apex predator. Future work can build upon this study by investigating how muscular driven top speeds may affect ontogenetic niche partitioning and prey species regularly targeted by adult T. rex.

paleontology↗

bioRxiv2022

Design of a systemic small molecule clinical STING agonist using physics-based simulations and artificial intelligence

The protein STING (stimulator of interferon genes) is a central regulator of the innate immune system and plays an important role in antitumor immunity by inducing the production of cytokines such as type I interferon (IFN). Activation of STING stems from the selective recognition of endogenous cyclic dinucleotides (CDNs) by the large, polar, and flexible binding site, thus posing challenges to the design of small molecule agonists with drug-like physicochemical properties. In this work we present the design of SNX281, a small molecule STING agonist that functions through a unique self-dimerizing mechanism in the STING binding site, where the ligand dimer approximates the size and shape of a cyclic dinucleotide while maintaining drug-like small molecule properties. SNX281 exhibits systemic exposure, STING-mediated cytokine release, strong induction of type I IFN, potent in vivo antitumor activity, durable immune memory, and single-dose tumor elimination in mouse models via a Cmax-driven pharmacologic response. Bespoke computational methods - a combination of quantum mechanics, molecular dynamics, binding free energy simulations, and artificial intelligence - were developed during the course of the project to design SNX281 by explicitly accounting for the unique self-dimerization mechanism and the large-scale conformational change of the STING protein upon activation. Over the course of the project, we explored millions of virtual molecules while synthesizing and testing only 208 molecules in the lab. This work highlights the value of a multifaceted computationally-driven approach anchored by methods tailored to address target-specific problems encountered along the project progression from initial hit to the clinic.

cancer biology↗