Cell membranes are known to form domains in order to switch on and off cellular function. For example certain proteins adsorb to membranes only in cholesterol rich domains. Inspired by the ability of these biological environments to locally segregate in order to optimize function this project aims to understand at the molecular level how to drive domain formation in mixtures of amphiphilic molecules in order to design switch able and selective binding environments. The proposed work involves the development and applications of theoretical approaches that will enable the study of the thermodynamics and kinetics of domain formation to optimize or inhibit ligand-receptor binding. The theoretical methodologies will include atomistic molecular dynamics simulations and the equilibrium and kinetic version of a molecular theory that the PI and collaborators have been developing for more that 20 years. The proposed work is divided into three parts: 1) Prediction of the phase behavior of amphiphilic mixtures, where the molecules will be considered with and without polymer head-groups. 2) Systematic study of the equilibrium ligand-receptor binding in the presence (and absence) of polymeric spacers. These studies will be carried out for ligands attached to the surface of nanoparticles of spherical and cylindrical geometries as well as to planar surfaces/interfaces. 3) Selective kinetic studies on: i) the formation of domains in amphiphilic systems driven by changes in the environment; ii) ligand-receptor binding and iii) ligand-receptor binding upon domain formation. The proposed systematic studies will enable to build general guidelines for the optimal design of surfaces and interfaces that can find applications in biomaterials, biosensors and drug carrier systems as well as the surface modification on nanoparticles that can optimize binding for imaging or separations.
Intellectual Merit:
The molecular design of responsive interfaces for optimal binding combines multidisciplinary expertise in engineering, physics, chemistry and biology. The proposed work has the dual purpose of fundamental understanding that can then be applied in the molecular design of materials with novel interfacial properties. The work combines: 1) the fundamental understanding of the phase behavior, kinetic and structural properties of complex mixtures of amphiphilic molecules with polymers containing chemical moieties with specific binding capabilities. This understanding may also shed light on the composition-function relationship in cell membranes. 2) The findings from this work can be directly applied in the rational design of biomaterials, biosensors and drug carriers. The study of these complex mixtures requires the understanding of equilibrium and time dependent properties. The time dependent behavior spans over many orders of magnitude in time. The proposed work, thus, combines atomistic simulations that are excellent for short time scales with time dependent molecular theory that enables the study of very long times maintaining a molecular level description of the mixtures. The collaboration with the experimental groups of Profs. Thompson (Purdue), Genzer (NCSU) and Shull (Northwestern) will provide the theoretical work with realistic checks at all stages of the work.
Broader Impact:
The proposed work will provide research educational experiences for graduate and undergraduate students. The PI plans to use the resources available at Northwestern University to attract women and underrepresented minorities to participate in this project. These resources include the REU program administered by Northwestern MRSEC and the Summer Research Opportunity Program. The research outcomes of the proposed work will be integrated into the new courses that the PI is developing since joining the engineering school at Northwestern. The findings from the research will be published in peer-reviewed journals and a popular version of the findings will be available in the PI's web site. The proposed work also includes the development of software to apply the molecular theory. The programs will be available for download from the PI's web site and will be aimed for the use by non-expert due to the large multidisciplinary application of the proposed work.
Lipid molecules are the main component of cell membranes and are composed by two parts, one that likes water chemically bound to another that does not dissolve in water. Thus, these molecules form bilayers that serve to control the traffic of molecules in and out of biological cells. The molecular factors that determine the properties of lipid layers are important in the understanding of the properties of biological cell membranes and it serves as an important building block in the design of drug delivery systems. The interactions of materials that carry drug with cells are of primary importance to deliver the drug to the appropriate cell. The work carried out focused on understanding how mixtures of lipids can be designed to interact with cell membranes for optimal drug delivery. We developed theoretical methods that enable the determination of the structure and interactions of different lipid mixtures. We have shown how the proper chemical structure of the molecules provides stability under different condition, such as pH and temperature. Furthermore, we demonstrated the importance of controlling the environment very close to the lipid layers. For example, the presence of charged surfaces can be detriment for the formation of liquid layers resulting in a transformation to a solid state with large changes on the permeability of the film. Furthermore, we show how different compositions of lipids can lead to varying interactions with protein anchors. A major finding of the work is how identical molecules containing acidic groups can separate into domains of different structures in which the local pH is very different from that of the solution in contact with it. This provides guidelines for constructing environment of nanometric dimensions with very different chemical environments that the surrounding media. This is important in the design of biosensors and drug delivery systems. On the educational side this project provided training to undergraduate, graduate students and a postdoctoral associate on interdisciplinary research at the interface of chemical and biological engineering, physics, chemistry and biology. The students were involved in computational research with strong interaction with experimental components and thus they are prepared for independent carriers on research and industry in the biochemical and biomedical fields.
