Bottom-Up Coarse-Grained Models for Intrinsically Disordered Proteins

Abstract

Intrinsically disordered proteins (IDPs) have recently become a popular topic of study in the protein science community due to their role processes such as cellular signaling and liquid-liquid phase separation (LLPS). A number of coarse-grained models for IDPs have been recently been developed. These models are typically of the top-down variety; they are parameterized to reproduce a set of experimental information. While these models have been effective for providing a computational basis for the study processes such as LLPS, they must rely on assumptions about the interactions between coarse-grained sites due to the lack of microscopic information. This is contrasted with bottom-up coarse-graining, which relies on data from a higher resolution source, like an atomistic molecular dynamics trajectory, to parameterize the model. Using high-quality atomistic data generated from recently developed force-fields, we have developed multiscale coarse-grained and relative entropy minimization coarse-grained models of several residues common among IDPs. These models are not limited to the standard Lennard-Jones and screened electrostatic functional forms typically used in top-down coarse-grained models. This model is also able to better capture the effects of solvation on the IDP. These new functional forms provide a basis to create a full interaction matrix that is based on mixing rules determined for a small number of residues. This new model creates higher fidelity coarse-grained model for the study LLPS as well as providing a basis-set for parameterizing interactions of new top-down models.