Population-based heteropolymer design to mimic protein mixtures.

Biological fluids, the most complex blends, have compositions that constantly vary and cannot be molecularly defined1. Despite these uncertainties, proteins fluctuate, fold, function and evolve as programmed2-4. We propose that in addition to the known monomeric sequence requirements, protein sequences encode multi-pair interactions at the segmental level to navigate random encounters5,6; synthetic heteropolymers capable of emulating such interactions can replicate how proteins behave in biological fluids individually and collectively. Here, we extracted the chemical characteristics and sequential arrangement along a protein chain at the segmental level from natural protein libraries and used the information to design heteropolymer ensembles as mixtures of disordered, partially folded and folded proteins. For each heteropolymer ensemble, the level of segmental similarity to that of natural proteins determines its ability to replicate many functions of biological fluids including assisting protein folding during translation, preserving the viability of fetal bovine serum without refrigeration, enhancing the thermal stability of proteins and behaving like synthetic cytosol under biologically relevant conditions. Molecular studies further translated protein sequence information at the segmental level into intermolecular interactions with a defined range, degree of diversity and temporal and spatial availability. This framework provides valuable guiding principles to synthetically realize protein properties, engineer bio/abiotic hybrid materials and, ultimately, realize matter-to-life transformations.

Engineering Low Volume Resuscitants for the Prehospital Care of Severe Hemorrhagic Shock.

Globally, traumatic injury is a leading cause of suffering and death. The ability to curtail damage and ensure survival after major injury requires a time-sensitive response balancing organ perfusion, blood loss, and portability, underscoring the need for novel therapies for the prehospital environment. Currently, there are few options available for damage control resuscitation (DCR) of trauma victims. We hypothesize that synthetic polymers, which are tunable, portable, and stable under austere conditions, can be developed as effective injectable therapies for trauma medicine. In this work, we design injectable polymers for use as low volume resuscitants (LVRs). Using RAFT polymerization, we evaluate the effect of polymer size, architecture, and chemical composition upon both blood coagulation and resuscitation in a rat hemorrhagic shock model. Our therapy is evaluated against a clinically used colloid resuscitant, Hextend. We demonstrate that a radiant star poly(glycerol monomethacrylate) polymer did not interfere with coagulation while successfully correcting metabolic deficit and resuscitating animals from hemorrhagic shock to the desired mean arterial pressure range for DCR - correcting a 60 % total blood volume (TBV) loss when given at only 10 % TBV. This highly portable and non-coagulopathic resuscitant has profound potential for application in trauma medicine.

Solvent Remodeling in Single-Chain Amphiphilic Heteropolymer Systems.

This work demonstrates the remodeling of single-chain nanoparticles (SCNPs) upon a transition to organic solvent through molecular dynamics simulations. Methacrylate-based random heteropolymers (RHPs), assembled via transient noncovalent linkages in water, have shown promise in an assortment of applications that harness their bio-inspired properties. While their molecular behavior has been broadly characterized in aqueous environments, many newer applications include the use of organic solvent rather than bio-mimetic conditions. The polymer assemblies, typically driven by the hydrophobic effect in water, are less well understood in nonaqueous solution. Here, a specific RHP system is examined which forms compact globular morphologies in highly polar or highly nonpolar environments while adopting extended conformations in solvents of intermediate polarity. The pivotal role of electrostatic interactions between charge groups in low dielectric mediums is also observed. Finally, high temperature anneal cycles are compared to room temperature transformations to illuminate barriers to remodeling upon environmental changes.