CAREER: Multiscale Simulation of Solute Transport in Hydrogels

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PROJECT SUMMARYCTS-0544933; Drexel University; Abrams, Cameron F Title: CAREER: Multiscale Simulation of Solute Transport in Hydrogels This CAREER project is broadly concerned with understanding the links between molecular structure and macroscopic properties of matter. The scientific goal of this project is to use multiscale molecular simulation to understand diffusive transport of protein molecules in hydrogels. The research program is concerned with two important and perhaps interrelated effects: (1) The role of electrostatics, manifest particularly in (a) specific solute/polymer interactions that affect solute diffusion, and (b) stability ofsolute complexes, and (2) the role of solute conformational variability. A better understanding of both of these effects is required for rational design of hydrogels for many drug delivery and tissue engineering applications. The project focuses focus specifically on insulin in acrylic polyelectrolyte hydrogels, seeking to answerthe following question: Under what conditions are (a) association of hexameric insulin with polymer chains of the gel and (b) the stability of the hexameric insulin against dissociation in pH-sensitive hydrogels determining factors of its diffusivity? A major thrust is overcoming length and time-scale restrictions of traditional molecular simulation methods in order to capture mechanisms underlying slow diffusive transport. To this end, the PIs will use a simulation approach integrating traditional generic-level molecular descriptions of hydrogel polymer/solute systems with novel inhomogeneously resolved molecular models which introduce required atomic-level specificity when and where necessary. The inhomogeneous resolution method couples an explicit polymer/solute/water subdomain to a surrounding gel comprised of systematically coarsened bead-spring chains with coarse-grained solvent. At all levels of resolution, molecular dynamics (MD) simulations with judicious application of free-energy barriercrossing techniques will enable the study of activated diffusional processes. The PI first addresses the two effects with generic MD (i.e., using studies in which polymers are bead-spring chains and solutes are spherical or bead-spring objects). Elements used in the coarse-grained study are systematically refined into an inhomogeneous resolution description of insulin in poly(acrylic acid) and poly(methacrylic acid) gels.INTELLECTUAL MERIT: Detailed models such as those used in this project are ultimately necessary for a complete understanding of insulin transport in novel drug delivery protocols, yet fully atomically resolved models are enormously expensive. The push to develop inhomogenously resolved models, balancing generality and specificity,represents a relatively new strategy in incorporating the required specificity. Yet it is not a priori clear how best to construct resolution boundaries. Furthermore, statistically relevant results can only be guaranteed by employing suitable path sampling techniques. Yet these techniques remain largely untested for large-scale systems. There are therefore significant challenges in realizing the goals of this project, as well as opportunities to contribute to the broader development of simulation techniques foraddressing many other problems in molecular-scale biological physics. The combined approach involving both generic and specific inhomogeneously resolved systems is designed to meet these challengesBROADER IMPACTS: Using computation to understand molecular structure and its link to macroscopic properties is also a central theme in the educational initiative of this CAREER program. The PI will develop a new software tool which uses interactive 3D visualization to teach concepts of molecular structure to high school chemistry students. The tool will take its place among a growing selection of computer-based instructional tools now becoming prevalent at the high-school level for increasing the interactivity of instruction in the basic sciences. A plan for developing, testing, and deploying the software involving local teachers, Drexel undergraduates, and local volunteers is discussed. Development will follow guidelines suggested by authors of recent scientific studies of the effectiveness of interactive multimedia applications in high school chemistry courses, for which the applications used are not freely available or no longer supported. The educational initiative will preferentially benefit groups historically underrepresented in the sciences and engineering, because the student population of the Philadelphia public school system is 65% African-American and 15% Hispanic.