The focus of our research is in the molecular modeling of biointerphases. Our work is aimed at the fundamental understanding of the properties of complex molecular systems that encompass problems at the interface between biology, chemistry, physics and materials science. Our group concentrates on the development and application of theoretical approaches that enable the study of the systems of interest at the molecular level. Most of our projects are carried out in close collaboration with experimental collaborators. Our theoretical work has the dual purpose of: 1) the fundamental understanding of what are the molecular factors that determine the properties and behavior of the interactions between biological environments and synthetic systems, and 2) the ability to predict in a quantitative way experimental systems in order to use the theoretical approaches as a device tool for the engineer of new materials, such as biocompatible materials and drug carriers.

Protein Adsorption

One of the major projects that our group has been working in the last few years relates to the general problem of understanding the driving forces for protein adsorption and how to find mechanisms that enable the control of the adsorption process. For example, surfaces of biomaterials need to be protected from protein adsorption since this is the first step in the triggering of immunological responses by the body.

To this end we developed a general theoretical framework that enables us to study the thermodynamics and kinetics of protein adsorption. This is a particularly challenging problem since the time scale for the adsorption process may be in the hours. Our theoretical framework enables us to predict quantitatively the adsorption isotherms of lysozyme and fibrinogen on surfaces with grafted polyethylene oxide and we have described the mechanism by which grafted polymer layers prevent/reduce protein adsorption.

We are using our understanding of the kinetics of adsorption and desorption to propose surface modifiers that can be used in the design of controlled release devices. We are continuing our attempt to understand the link between detailed molecular organization and protein adsorption. To this end we are using detailed atomistic simulations the role of water on the protein-surface interactions.

Biophysics of Lipids

Bolalipids We are studying the structural, mechanical and phase behavior of layers formed by mixtures of linear and bolalipids. The aim of this work is to understand and the fundamental level how molecules that have two head-groups anchored by a flexible hydrophobic backbone changes the properties of the lipid layers as compared to the linear counterparts. Namely, what is the fraction of bolalipids that are found across the layer as compared to forming a U shape? What are the elastic properties of the layers? What is the thermodynamic stability of bola and linear lipids? The understanding of these properties will be used (in collaboration with our experimental collaborators, Profs. D. Thompson and C. Hrycina) in the building of integral membrane protein based sensors.

Spontaneous liposome formation in mixtures of pegolated lipids The goal in this project is to understand the conditions necessary for the formation and stability of spherical liposomes formed by mixtures of lipids with lipids conjugated with PEG (poly ethylene glycol). The idea is to find the optimal conditions for stabilization of the aggregates to be used as drug carriers and their destabilization upon arrival to target cells. From the fundamental point of view it is a fascinating problem in which the understanding of the coupling between curvature and composition is governed by the nature of the polymers in the lipid head-groups and the mixing of the lipid chains.

Membrane-solute interactions ty_research_scaledA nearby image shows doxorubicin, an anti-cancer drug, deforming a bilayer composed of DPPC (green) and cholesterol (orange). By calculating the energy barrier needed for translocation of the drug across the membrane, we begin to understand the relationship between bilayer composition (i.e. cholesterol fraction) and the release profile of a drug. The idea is that for every drug there is a particular liposomal membrane composition that optimizes the balance of toxicity and efficacy.

Lipid-Poloxamer mixtures Inspired by the experimental work of Prof. Ka-Yee Lee at the University of Chicago we have been studying the interactions between lipid molecules and block copolymers. We have found that the addition of hydrophobic-hydrophilic block copolymers to a dilute lipid monolayer results in the clustering of the lipid that tend to be organized in well-ordered domains. The results from the lipid-polymer mixtures have implications for the formation of ordered domains of nanoparticles in two dimensions. We are currently studying the structure of the polymer molecules within a lipid bilayer with the aim to understand the role that poloxamers play in sealing cell membranes.

Lipid phase behavior In collaboration with Dr. R. Elliot and Prof. M. Schick we are studying the phase behavior of mixtures of saturated and unsaturated lipids as well as ternary mixtures of saturated-unsaturated-cholesterol. We predict liquid-liquid coexistence due to differences in lipid and cholesterol packing that may be related to the presence of rafts in biological membranes. We are continuing these studies and plan to study the formation of domains within a membrane.

Biologically Inspired Nanomaterials

Aggrecans We are studying the structure and interactions between aggrecans. These are bottlebrush like structures formed by tethered polysaccharides on a protein backbone. Aggrecans are one of the main components of cartilage. Thus it has unique mechanical properties whose understanding will inspire the development of synthetic materials with similar properties. This work is done in collaboration with the experimental groups of Profs. J. Genzer, A. Grodzinsky and C. Ortiz. To understand these systems we have to understand the role of the nanosize cylindrical tethering surface as well as the changes on acid-base equilibrium of the saccharide groups in a highly inhomogeneous environment.

Polymer stabilized carbon nanotubes as an application of the role of geometry on the properties of tethered polymers we are studying the ability of tethered polymers on surfaces of carbon nanotubes to disperse individual tubes in solution. This work, carried out in with our experimental collaborator Prof. R. Yerushalmi-Rozen, provides guidelines for the type of polymers that will enable nanotubes dispersion without modifying the intrinsic properties of the tubes.

Ligand-receptor interactions how does the binding between a ligand and receptor changes when the ligand is attached to a surface by a polymer spacer? This is one of the questions that we are addressing in order to learn how to control ligand-receptor interactions in confined environments. We are finding that spacers have an optimal surface coverage that enhances the amount of proteins bound and we are predicting ways to orient the bound proteins.

Fusion peptide interactions. In collaboration with the Thompson group at Purdue University, we study the ability of fusion peptides to induce fusion as functional groups on liposomal carriers, using Förster resonance energy transfer (FRET). Atomistic molecular dynamics and Monte Carlo simulations are helping us understand the relationship between peptide clustering and peptide fusogenicity. The end goal is to design carriers that do not fuse at physiological pH (during circulation), but do fuse at low pH (endosomal conditions).

Responsive Polymer Layers

Some types of polymer molecules can change their average properties as a response to changes in the environment. For example, thermoresponsive polymers collapse upon changes of temperature; polyelectrolytes change stretch upon changes in the ionic strength of the solution. We are modeling the behavior of a variety of responsive polymer systems in which the chain molecules are end-tethered to a surface or an interface. For example, in collaboration with the experimental group of Prof. J. Genzer, we are studying the ability of thermoresponsive polymers to adsorbed nanoparticles upon changes in temperature. A very important fundaments question that we aim to answer studying this family of systems is what is the coupling between the conformational degrees of freedom of the chains, the local density, the electrostatic interactions and the possibility of shifting the charge of the polymer segments through changes in the external conditions.

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