Protein association in a multicomponent lipid environment

University Of Houston, Houston TX

Investigators

Abstract

CBET-1067356 Doxastakis, Emmanouil Protein association in membranes is a process of major physiological and technological significance. Association of individual helices in a membrane environment is a critical step towards the assembly of a functional integral protein. Regulation of this process provides a path to modulate signal transduction mechanisms and cell proliferation. Association of proteins is also a required step for the successful formation of stable artificial pores and membrane redox proteins. Current state of knowledge on the factors that control protein association is significantly limited. While several studies have provided a qualitative view of the underlying thermodynamics, there is a clear need of quantitative predictive tools that will offer estimates of structural and thermodynamic properties for a specific amino-acid sequence in a lipid membrane. The hypothesis is that computational methods can serve this purpose if both amino-acid detail and membrane composition are accounted for. These factors control the function and phase behavior of transmembrane proteins. To test the hypothesis, the investigators will design and perform extensive parallel Monte Carlo simulations with the transmembrane sequence of Glycophorin A and the transmembrane domains of the epidermal growth factor receptor family in lipid membranes composed by cholesterol and phospholipids. Results from the first system will be directly compared to available experimental data while predictions for the second will increase our knowledge on contributions of transmembrane sequences to the association of an important family of receptors. Intellectual merit: In this interfacial-related and health-related project, the investigators will provide a fundamental understanding on the factors controlling aggregation of small transmembrane helices in lipid membranes. Molecular simulations will examine the effect of amino-acid sequence, quantify local concentrations not accessible to experimental techniques and provide estimates of the association thermodynamics. The project will develop parallel Monte Carlo algorithms that reach beyond current techniques examining sequence-specific association in explicit multicomponent membranes. Furthermore, it will produce new knowledge on the behavior of transmembrane domains of the family of epidermal growth factor receptors in different microenvironments ranging from single-component fluid lipid bilayers to ordered membranes reminiscent of lipid rafts. Broader impacts: Research results will have a broader societal impact by developing predictive computational tools to study protein association without the need to resort to the current limited knowledge of membrane protein structures. The development of such tools will advance our ability to design new functional proteins with applications in biotechnology. Additionally, the extracted estimates on the association affinity of transmembrane sequences of receptor proteins in membranes will assist the design of peptides acting as inhibitors. Finally, the successful implementation of advanced modeling techniques represents a multidisciplinary problem-solving activity through computational tools. The PI aims to inspire students from underrepresented groups to learn about modeling and engage them into research activities with simulation methods within the scope of the proposed research. Using existing opportunities at the University of Houston, the PI will work with high-school teachers and undergraduate students on short-term projects aiming to extract atomistic details of protein complexes with the resulting structures made available to the community.