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Exploring the Components of Pulmonary Surfactant using Computational Techniques to Engineer Therapeutics

Hypothesis: We hypothesize that the components of pulmonary surfactant can be enhanced and utilized to engineer new therapeutics for the treatment of various diseases.

Different Pulmonary Surfactant Compositions and Their Uses

Motivation

Pulmonary surfactant research is essential because it has the potential to develop novel therapeutics for diseases which affect millions of people worldwide.

Methods

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Programs

Program 1:

The structure and function of surfactant immunoproteins for the engineering of potential therapeutics

The immunoproteins SP-A and SP-D are part of a group known as collagen C-type lectins which are found throughout the body. The C-type lectins, part of the body’s natural immune response, including SP-A, SP-D, and MBL, are known for their ability to interact with the pathogen by binding the pathogenic surface glycan. They play an important role in the innate immune system to inhibit pathogens' activities.

Research Paper

Elucidating the enhanced binding affinity of a double mutant SP-D with trimannose on the influenza A virus using molecular dynamics

Program 2:

The study, understanding, and modeling of the monolayer to bilayer transition of PS to engineer a more effective synthetic PS

This program is working to understand the impact PS proteins and lipids have on the monolayer to bilayer transition during the breathing process through understanding how PS proteins (SP-B and SP-C) and PS lipids (zwitterionic saturated and unsaturated phospholipids, cholesterol, and negative unsaturated phospholipids) impact the monolayer to bilayer transition and how the surface tension changes.

Program 3:

Modeling drug delivery mechanisms.

This program delves into the complexities of micellar and bilayer molecular structures, primarily focusing on enhancing our understanding of drug delivery and their interactions with the pulmonary surfactant (PS) lipid layer. This research is crucial for developing more effective and targeted drug delivery methods, especially in the context of the respiratory system, an increasingly targeted area for drug delivery due to its high permeability, large adsorptive surface area, and good blood supply. While drugs are often slowly cleared through the lungs, resulting in poor absorption, our program aims to exploit this knowledge and utilize the moieties of pulmonary surfactant as potential drug carriers for inhalation therapy.

Program 4:

Engineering computational techniques and methods for the study of biological interfaces.

We are tracking and refining the methods we use to model pulmonary surfactant, such as best computational techniques and force fields, as we accomplish programs 1-3. For example, one project is developing a hybrid force field for proteins. Our group is working to develop a hybrid force field, an inversion of the previous work done by Kar and Feig, that involves coarse-graining the backbone of a protein and atomistically modeling side chains to utilize both MC and MD in a single simulation protocol, alternating between the two for optimal equilibration efficiency, and employing force fields, already well-known for their accuracy, to model the surfactant proteins of interest. We are working to create a program allowing for any partitioning and modeling of biological systems while enabling users to obtain parameters for their choice of coarse-grained or atomistic beads. If needed, our group will extend the existing force fields to allow for the study of such complex biological systems.

Program 5:

Engineering tools and techniques to make STEM research accessible to the blind.

We are engineering tools and techniques to make STEM research accessible for individuals who are blind. As a blind scientist myself, it is important to engineer these tools for conducting and sharing research. We are collaborating with Bryan Shaw at Baylor University to pioneer accessible technologies, including the creation of lithophanes and other innovative methods, to transform the communication of scientific information.

• link to NPR

• Science Advances paper

• NIGMS blog post