Small residues with relatively exposed backbone peptide bonds include Gly, Ser, Thr and Pro. Sidechains with pi bonds include Tyr, Phe, Trp, His, Gln, Asn, Glu, Asp and Arg. Clearly, a number of physical interactions may be sufficient for driving phase separation without being universally necessary, and a better understanding of these interactions is needed to define the balance of forces biological systems use for driving protein phase transitions.Īlthough pi-pi interactions are commonly associated with aromatic rings, where interaction energy is thought to involve induced quadrupolar electrostatic interactions ( Sherrill, 2013), π (pi) orbitals of bonded sp 2-hybridized atoms are also found in peptide backbone amide groups and sidechain amide, carboxyl or guanidinium groups. The Phe-Gly repeats in FG nucleoporins similarly indicate pi-pi interactions, but the lack of aromatics in elastins and designed phase-separating sequences ( Quiroz and Chilkoti, 2015) seems to suggest that they are not essential. The abundance of Phe-Gly/Gly-Phe and Arg-Gly/Gly-Arg dipeptides in Ddx4 and the fact that Phe to Ala mutations inhibit phase separation also point to pi-pi and/or cation-pi interactions. For Ddx4, electrostatic interactions between charge blocks has been demonstrated ( Nott et al., 2015 Lin et al., 2016). Multivalent ( Li et al., 2012 Pierce et al., 2016) electrostatic ( Pak et al., 2016 Lin et al., 2016) and cation-pi ( Nott et al., 2015 Kim et al., 2016 Sherrill, 2013) interactions and the hydrophobic effect ( Yeo et al., 2011) have all been proposed to contribute to IDR phase separation, the latter suggested to be dominant for tropoelastin ( Luan et al., 1990). The underlying physical principles and chemical interactions that drive phase separation in these IDRs are not well understood. However, many phase-separating proteins contain large intrinsically disordered protein regions (IDRs) with low complexity sequences that do not form stable folded structure (reviewed in ), including the Nephrin intracellular domain (NICD) ( Pak et al., 2016), polyglutamine tracts ( Crick et al., 2013), tropoelastin ( Yeo et al., 2011), FUS ( Burke et al., 2015 Kato et al., 2012), Ddx4 and the homologous LAF-1 ( Nott et al., 2015 Elbaum-Garfinkle et al., 2015) and FG-repeat nucleoporins ( Frey et al., 2006). For some systems, multivalent interactions between modular binding domains and cognate peptide motifs underlie phase-separation ( Li et al., 2012 Banjade and Rosen, 2014). Protein phase separation has important implications for cellular organization and signaling ( Mitrea and Kriwacki, 2016 Brangwynne et al., 2009 Su et al., 2016), RNA processing ( Sfakianos et al., 2016), biological materials ( Yeo et al., 2011) and pathological aggregation ( Taylor et al., 2016). We present a phase separation predictive algorithm based on pi interaction frequency, highlighting proteins involved in biomaterials and RNA processing. We found that pi-pi interactions involving non-aromatic groups are widespread, underestimated by force-fields used in structure calculations and correlated with solvation and lack of regular secondary structure, properties associated with disordered regions. Known phase-separating proteins are enriched in pi-orbital containing residues and thus we analyzed pi-interactions in folded proteins. However, forces promoting the more common phase separation of intrinsically disordered regions are less understood, with suggested roles for multivalent cation-pi, pi-pi, and charge interactions and the hydrophobic effect. Multivalent interactions of modular binding domains and their target motifs can drive phase separation. Protein phase separation is implicated in formation of membraneless organelles, signaling puncta and the nuclear pore.
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