(4dj) Understanding Unique Properties of Zwitterionic Materials From Their Molecular Structures

Resisting nonspecific protein adsorption in complex media is critically important for a wide range of applications such as drug/gene delivery, therapeutic protein conjugation, biosensors, and marine coatings. Polyethylene glycol has been extensively studied and widely used for these purposes, but the amphiphilic feature of polyethylene glycol brings negative effects on bioactivity and affinity. Zwitterionic polycarboxybetaine and polysulfobetaine are a new type of superhydrophilic materials that resist nonspecific protein adsorption in complex media such as whole blood. However, the nonfouling mechanisms for zwitterionic materials are not yet illustrated.

The properties of zwitterionic moiety determine the performance of zwitterionic materials. For instance, the hydration of zwitterionic moiety is considered as the main source of the nonspecific protein resistance of zwitterionic materials. Other important properties include ion and protein interactions. Zwitterionic moieties can vary their molecular structure mainly in three respects: cationic group, anionic group, and carbon spacer length between them. Varying any of these three structural aspects will change the properties of the zwitterionic moieties. Understanding how molecular structure dictates the properties of zwitterionic moieties is therefore fundamentally important not only to reveal the nonfouling mechanisms of zwitterionic materials, but also to perform a rational design of new zwitterionic materials. In this work, we studied the effects of the molecular structure of zwitterionic moieties on their molecular properties with quantum mechanical calculations and molecular dynamics simulations.

Quantum mechanical calculations were used to examine the interference between charged groups in a zwitterionic moiety, and to develop a set of force field parameters for zwitterionic moieties. With the developed force field, we studied effects of the cationic group, anionic group and carbon spacer length on the hydration of zwitterionic moieties using molecular dynamics simulations, free energy perturbation, and metadynamics simulations. Analysis of hydration numbers, residence time of water molecules, and free energy shows that the above three structure features have distinct effects on zwitterionic moieties. We also studied the ion interactions of zwitterionic moieties by analyzing the zwitterion-ion association structure, dynamics and free energy. The simulation results show an important role for the anionic group in specific cation interactions of zwitterionic moieties. Carboxybetaine and sulfobetaine showed different ion preferences and self-associations due to different combinations of charged groups. Protein interactions of zwitterionic moieties were studied in comparison with protein interactions of the (ethylene glycol)₄ moiety. We performed extensively long molecular dynamics simulations to investigate any specific moiety-protein interactions and their influence on protein surface area, flexibility and structure. The simulation results show that the (ethylene glycol)₄ moieties influence protein structure and dynamics differently from zwitterionic moieties. A series of metadynamics simulations showed that the (ethylene glycol)₄ and zwitterionic moieties also have different effects on the hydrophobic interactions in a biological system. These simulation studies demonstrate how the molecular structure of zwitterionic moieties determines their molecular properties, provide insight into the nonfouling mechanisms of zwitterionic materials, and offer a guideline for the rational design of zwitterionic materials.