Amino Acid-Dependent Material Properties of Tetrapeptide Condensates

Zhang, Yi; Prasad, Ramesh; Su, Siyuan; Lee, Daesung; Zhou, Huan-Xiang

doi:10.1101/2024.05.14.594233

Cited by 6 publications

(3 citation statements)

References 45 publications

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“…18 Recently, all-atom MD simulations provided explanations for wide variations in phase equilibrium and material properties among condensates of tetrapeptides with different amino-acid compositions. 34 These and other simulations 35 show that all attractive residue-residue contacts contribute to the drive for phase separation.…”

Section: Introductionmentioning

confidence: 69%

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Direct and Indirect Salt Effects on Homotypic Phase Separation

MacAinsh,

Dey,

Zhou

2024

Preprint

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The low-complexity domain of hnRNPA1 (A1-LCD) phase separates in a salt-dependent manner. Unlike many intrinsically disordered proteins (IDPs) whose phase separation is suppressed by increasing salt concentrations, the phase separation of A1-LCD is promoted by > 100 mM NaCl. To investigate the atypical salt effect on A1-LCD phase separation, we carried out all-atom molecular dynamics simulations of systems comprising multiple A1-LCD chains at NaCl concentrations from 50 to 1000 mM NaCl. The ions occupy first-shell as well as more distant sites around the IDP chains, with Arg sidechains and backbone carbonyls the favored partners of Cl- and Na+, respectively. They play two direct roles in driving A1-LCD condensation. The first is to neutralize the high net charge of the protein (+9) by an excess of bound Cl- over Na+; the second is to bridge between A1-LCD chains, thereby fortifying the intermolecular interaction networks in the dense phase. At high concentrations, NaCl also indirectly strengthens π-π, cation-π, and amino-π interactions, by drawing water away from the interaction partners. Therefore, at low salt, A1-LCD is prevented from phase separation by net charge repulsion; at intermediate concentrations, NaCl neutralizes enough of the net charge while also bridging IDP chains to drive phase separation. This drive becomes even stronger at high salt. Based on this understanding, four salt effect types on the phase separation of IDPs can be predicted based on their amino-acid compositions.

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Section: Introductionmentioning

confidence: 69%

“…15 Recently, all-atom MD simulations provided explanations for wide variations in phase equilibrium and material properties among condensates of tetrapeptides with different amino-acid compositions. 29…”

Section: Introductionmentioning

confidence: 99%

Direct and Indirect Salt Effects on Homotypic Phase Separation

MacAinsh,

Dey,

Zhou

2024

Preprint

Self Cite

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“…Gly and Ser suppress phase separation (10,33,42). Recent measurements of the threshold concentration produced the following order for the propensity of phase separation by eight nonpolar amino acids in homotetrapeptides of the form XXssXX (ss: backbone disulfide bond): Trp > Phe > Leu > Met > Ile > Val > Ala > Pro (43). This order is the same as that of the 𝑞 parameters, except that the 𝑞 values of Ile and Val are in the second and last places, respectively.…”

Section: Discussionmentioning

confidence: 98%

Predicting the Sequence-Dependent Backbone Dynamics of Intrinsically Disordered Proteins

Qin

Zhou

2023

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Dynamics is a crucial link between sequence and function for intrinsically disordered proteins (IDPs). NMR spin relaxation is a powerful technique for characterizing the sequence- dependent backbone dynamics of IDPs. Of particular interest is the 15N transverse relaxation rate (R_2), which reports on slower dynamics (10s of ns up to 1 μs and beyond). NMR and molecular dynamics (MD) simulations have shown that local interactions and secondary structure formation slow down backbone dynamics and raise R_2. Elevated R_2 has been suggested to be indicators of propensities of membrane association, liquid-liquid phase separation, and other functional processes. Here we present a sequence-based method, SeqDYN, for predicting R_2 of IDPs. The R_2 value of a residue is expressed as the product of contributing factors from all residues, which attenuate with increasing sequence distance from the central residue. The mathematical model has 21 parameters, representing the correlation length (where the attenuation is at 50%) and the amplitudes of the contributing factors of the 20 types of amino acids. Training on a set of 45 IDPs reveals a correlation length of 5.6 residues, aromatic and long branched aliphatic amino acids and Arg as R_2 promotors whereas Gly and short polar amino acids as R_2 suppressors. The prediction accuracy of SeqDYN is competitive against that of recent MD simulations using IDP-specific force fields. For a structured protein, SeqDYN prediction represents R_2 in the unfolded state. SeqDYN is available as a web server at https://zhougroup-uic.github.io/SeqDYNidp/ for rapid R_2 prediction.

show abstract

Direct and Indirect Salt Effects on Homotypic Phase Separation

MacAinsh,

Dey,

Zhou

2024

Preprint

View full text Add to dashboard Cite

The low-complexity domain of hnRNPA1 (A1-LCD) phase separates in a salt-dependent manner. Unlike many intrinsically disordered proteins (IDPs) whose phase separation is suppressed by increasing salt concentrations, the phase separation of A1-LCD is promoted by > 100 mM NaCl. To investigate the atypical salt effect on A1-LCD phase separation, we carried out all-atom molecular dynamics simulations of systems comprising multiple A1-LCD chains at NaCl concentrations from 50 to 1000 mM NaCl. The ions occupy first-shell as well as more distant sites around the IDP chains, with Arg sidechains and backbone carbonyls the favored partners of Cl - and Na + , respectively. They play two direct roles in driving A1-LCD condensation. The first is to neutralize the high net charge of the protein (+9) by an excess of bound Cl - over Na + ; the second is to bridge between A1-LCD chains, thereby fortifying the intermolecular interaction networks in the dense phase. At high concentrations, NaCl also indirectly strengthens π-π, cation-π, and amino-π interactions, by drawing water away from the interaction partners. Therefore, at low salt, A1-LCD is prevented from phase separation by net charge repulsion; at intermediate concentrations, NaCl neutralizes enough of the net charge while also bridging IDP chains to drive phase separation. This drive becomes even stronger at high salt due to strengthened π-type interactions. Based on this understanding, four classes of salt dependence of IDP phase separation can be predicted from amino-acid composition.

show abstract

Amino Acid-Dependent Material Properties of Tetrapeptide Condensates

Cited by 6 publications

References 45 publications

Direct and Indirect Salt Effects on Homotypic Phase Separation

Direct and Indirect Salt Effects on Homotypic Phase Separation

Predicting the Sequence-Dependent Backbone Dynamics of Intrinsically Disordered Proteins

Direct and Indirect Salt Effects on Homotypic Phase Separation

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