Improved coarse‐grained model for studying sequence dependent phase separation of disordered proteins

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  • Roshan Mammen Regy
    Department of Chemical and Biomolecular Engineering Lehigh University Bethlehem Pennsylvania USA
  • Jacob Thompson
    Department of Chemical and Biomolecular Engineering Lehigh University Bethlehem Pennsylvania USA
  • Young C. Kim
    Center for Materials Physics and Technology Naval Research Laboratory Washington District of Columbia USA
  • Jeetain Mittal
    Department of Chemical and Biomolecular Engineering Lehigh University Bethlehem Pennsylvania USA

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<jats:title>Abstract</jats:title><jats:p>We present improvements to the <jats:bold>h</jats:bold>ydro<jats:bold>p</jats:bold>athy <jats:bold>s</jats:bold>cale (HPS) coarse‐grained (CG) model for simulating sequence‐specific behavior of intrinsically disordered proteins (IDPs), including their liquid–liquid phase separation (LLPS). The previous model based on an atomistic hydropathy scale by Kapcha and Rossky (KR scale) is not able to capture some well‐known LLPS trends such as reduced phase separation propensity upon mutations (R‐to‐K and Y‐to‐F). Here, we propose to use the Urry hydropathy scale instead, which was derived from the inverse temperature transitions in a model polypeptide with guest residues X. We introduce two free parameters to shift (Δ) and scale (<jats:italic>µ</jats:italic>) the overall interaction strengths for the new model (HPS‐Urry) and use the experimental radius of gyration for a diverse group of IDPs to find their optimal values. Interestingly, many possible (Δ, <jats:italic>µ</jats:italic>) combinations can be used for typical IDPs, but the phase behavior of a low‐complexity (LC) sequence FUS is only well described by one of these models, which highlights the need for a careful validation strategy based on multiple proteins. The CG HPS‐Urry model should enable accurate simulations of protein LLPS and provide a microscopically detailed view of molecular interactions.</jats:p>

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