Pi interactions in monomeric and phase-separated disordered state ensembles

点击翻译按钮获取中文摘要

Proteins are made up of a chain of different types of amino acid residues. While many proteins adopt a relatively static and ordered 3-dimensional shape in order to function, it has become clear that a large class of "disordered" proteins do not. They function in a highly flexible state, like strands of beads. Disordered proteins are found throughout biology, from viruses to plants and animals, and are associated with controlling critical biological events as well as in disease. They also form large liquid droplets, similar to oil droplets in salad dressing, that function in cellular organization in a process called “phase separation”. We have recently found that disordered protein amino acid residues having double bonds (pi-containing groups) are important for phase separation and we hypothesize that pi groups also significantly affect the structure of isolated disordered proteins. In order to better understand the nature of disordered proteins and how disordered proteins function in biology, particularly in organizing cells, atomic-level descriptions of disordered proteins and their phase-separated states are essential. While a static protein needs one structure to describe it, a disordered protein or liquid phase-separated state requires many structures (an ensemble) to represent it. Such extensive ensemble structural calculations are not possible with standard approaches. Thus, we have been developing the computer approach ENSEMBLE that calculates collections of structures that together are consistent with a large amount of experimental data and together represent the disordered protein. To address our goals of describing disordered and phase-separated states, we propose the following aims: (1) Design predictors of the compactness of disordered proteins and their propensities to phase-separate based on pi interactions. (2) Create new parameter sets for computational simulations of proteins to enable them to effectively model pi interactions. (3) Calculate ENSEMBLE models for an isolated and phase-separated protein for which we can obtain detailed NMR data in order to generate precise pictures of the structural features of these states and analyze the contributions of pi interactions to these features. Our efforts will significantly enhance the ability of the structural community to study these challenging disordered proteins that play essential biological roles, including in organizing the cell.