(648a) Atomistic Insight Towards the Effects of Conjugated Charged Polymers to ?-Chymotripsin

Enzymes play an important role in catalyzing biological reactions and eons of evolution has made enzymes highly efficient and selective. However, the complexity of enzymes makes it difficult to be used in different chemical environments and harsh conditions. Recent advances in the field of bioconjugation have opened up new synthesis methodologies to create new protein-polymer conjugates that potentially could overcome these drawbacks. Due to the delicate nature of proteins, it is important to understand how different polymer chains interact with protein surfaces and how chemical modification could affect the protein’s structure and dynamics.

In this work, we present how charged polymers such as zwitterionic-poly carboxybetaine acrylamide (pCBAA), positively charged-poly quaternary ammonium methacrylate (pQA), and negatively charged-poly sulfonate methacrylate (pSMA) interact with α-chymotrypsin (CT) while conjugated to it. Atomistic molecular dynamics simulations were carried out using the CHARMM C36m force field along with the CGenFF. Our atomistic simulations showed that conjugation of pSMA chains, to the surface lysine residues, destabilize the S1 binding pocket of CT while pQA and pCBAA chains stabilize the S1 binding pocket. Destabilization of the S1 binding pocket was identified to be due to interactions between pSMA chains and the activation loops (VI and VII) in CT. Our simulation data is in good agreement with experimental observations. In addition to structural changes within the protein, preferential polymer-protein interactions were studied as a function of contacts formed between each polymer and the surface protein amino acids. Contact analysis has revealed that pQA form the least amount of contacts with the protein surface compared to pSMA and pCBAA. This study illustrates the use molecular simulations to provide additional understanding for bioconjugates, but moreover the potential for the design of the next generation bioconjugates.