This proposal describes a concerted approach to the design, synthesis, and study of novel self- assembling molecules that are responsive to specific proteins. We take two complementary approaches. First, we develop design guidelines where proteins act as the trigger to deconstruct a higher order assembly to a lower order one (protein-responsive supramolecular disassembly). In this process, the assemblies transform from an effective host for hydrophobic small molecules to an ineffective one, which has implications in developing precise therapeutic responses to protein imbalances. In the second approach, we propose to develop molecular design guidelines that program a non-assembling polymer to transform into a higher order assembly in response to proteins (protein-templated self-assembly). The resultant nanoassemblies are programmed to release these encapsulated proteins in their pristine form in the presence of a specific biologically-relevant stimulus or due to a combination of such stimuli. Such a strategy will offer the ability to traffic proteins across a cellular membrane and release them inside cells, which has implications in several unmet challenges in biomedicine. In the protein-responsive supramolecular disassembly approach, we propose to develop versatile supramolecular assemblies that disassemble in response to specific proteins as stimuli. There have been great advances in stimuli-sensitive supramolecular assemblies. However, these have primarily focused on systems that respond to changes in factors such as pH, temperature, or redox conditions, which are secondary imbalances in biology. The most direct and primary indicator of imbalance in biology involves change in protein activity. Therefore, generating supramolecular assemblies that respond to proteins is exciting. Our primary objective is to obtain a better understanding of the structural factors that control the assembly/disassembly events in response to specific combinations of enzymatic and non-enzymatic proteins. In the protein-templated self-assembly approach, the templating proteins are incarcerated as guests into a matrix of host polymers. The resultant nanoassemblies are programmed to release these encapsulated proteins in their pristine form in the presence of a specific biologically-relevant stimulus or due to a combination of such stimuli. A key goal of the proposed research is to develop this into a new supramolecular platform that is useful for a broad range of soluble proteins, a capability that does not currently exist. The primary premise of the proposed research then is to develop a fundamental framework for custom-designing such supramolecular assemblies that can predictably encapsulate a protein, turn its function off, protect it from denaturation in non-native environments, and regain its native structure and function in response to a stimulus that is specific to the target environment. We will identify the structural factors that underlie the formation of these programmable molecular assemblies.
This premise of this project is to develop the fundamental understanding of the structural factors that underlie the formation and deconstruction of supramolecular assemblies, due to covalent and non-covalent interaction between polymers and proteins. These molecular assemblies are programmable, in that these can be triggered to disassemble in the presence of a biologically relevant stimulus or a combination such stimuli. Such programmed assemblies have utility in a broad range of unmet biomedical applications.