Liquid-liquid phase separation of short histidine- and tyrosine-rich peptides: sequence specificity and molecular topology
The increasing realization of the prevalence of liquid-liquid phase separation (LLPS) across multiple length scales of biological constructs, from intracellular membraneless organelles to extracellular load-bearing tissues, has raised intriguing questions about intermolecular interactions regulating...
| Main Authors: | , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2022
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| Online Access: | https://hdl.handle.net/10356/160365 |
| _version_ | 1811681537057357824 |
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| author | Lim, Jessica Kumar, Akshita Low, Kimberly Jia Yi Verma, Chandra Shekhar Mu, Yuguang Miserez, Ali Pervushin, Konstantin |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Lim, Jessica Kumar, Akshita Low, Kimberly Jia Yi Verma, Chandra Shekhar Mu, Yuguang Miserez, Ali Pervushin, Konstantin |
| author_sort | Lim, Jessica |
| collection | NTU |
| description | The increasing realization of the prevalence of liquid-liquid phase separation (LLPS) across multiple length scales of biological constructs, from intracellular membraneless organelles to extracellular load-bearing tissues, has raised intriguing questions about intermolecular interactions regulating LLPS at the atomic level. Squid-beak derived histidine (His)- and tyrosine (Tyr)-rich peptides (HBpeps) have recently emerged as suitable short model peptides to precisely assess the roles of peptide motifs and single residues on the phase behavior and material properties of microdroplets obtained by LLPS. In this study, by systematically introducing single mutations in an HBpep, we have identified specific sticker residues that attract peptide chains together. We find that His and Tyr residues located near the sequence termini drive phase separation, forming interaction nodes that stabilize microdroplets. Combining quantum chemistry simulations with NMR studies, we predict atomic-level bond geometries and uncover inter-residue supramolecular interactions governing LLPS. These results are subsequently used to propose possible topological arrangements of the peptide chains, which upon expansion can help explain the three-dimensional network of microdroplets. The stability of the proposed topologies carried out through all-atom molecular dynamics simulations predicts chain topologies that are more likely to stabilize the microdroplets. Overall, this study provides useful guidelines for the de novo design of peptide coacervates with tunable phase behavior and material properties. In addition, the analysis of nanoscale topologies may pave the way to understand how client molecules can be trapped within microdroplets, with direct implications for the encapsulation and controlled release of therapeutics for drug delivery applications. |
| first_indexed | 2024-10-01T03:42:31Z |
| format | Journal Article |
| id | ntu-10356/160365 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T03:42:31Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | ntu-10356/1603652022-07-20T03:13:29Z Liquid-liquid phase separation of short histidine- and tyrosine-rich peptides: sequence specificity and molecular topology Lim, Jessica Kumar, Akshita Low, Kimberly Jia Yi Verma, Chandra Shekhar Mu, Yuguang Miserez, Ali Pervushin, Konstantin School of Biological Sciences School of Materials Science and Engineering Bioinformatics Institute, A*STAR National University of Singapore Biological & Biomimetic Material Laboratory @ NTU Center for Sustainable Materials Engineering::Chemical engineering Aromatic Residues Proteins The increasing realization of the prevalence of liquid-liquid phase separation (LLPS) across multiple length scales of biological constructs, from intracellular membraneless organelles to extracellular load-bearing tissues, has raised intriguing questions about intermolecular interactions regulating LLPS at the atomic level. Squid-beak derived histidine (His)- and tyrosine (Tyr)-rich peptides (HBpeps) have recently emerged as suitable short model peptides to precisely assess the roles of peptide motifs and single residues on the phase behavior and material properties of microdroplets obtained by LLPS. In this study, by systematically introducing single mutations in an HBpep, we have identified specific sticker residues that attract peptide chains together. We find that His and Tyr residues located near the sequence termini drive phase separation, forming interaction nodes that stabilize microdroplets. Combining quantum chemistry simulations with NMR studies, we predict atomic-level bond geometries and uncover inter-residue supramolecular interactions governing LLPS. These results are subsequently used to propose possible topological arrangements of the peptide chains, which upon expansion can help explain the three-dimensional network of microdroplets. The stability of the proposed topologies carried out through all-atom molecular dynamics simulations predicts chain topologies that are more likely to stabilize the microdroplets. Overall, this study provides useful guidelines for the de novo design of peptide coacervates with tunable phase behavior and material properties. In addition, the analysis of nanoscale topologies may pave the way to understand how client molecules can be trapped within microdroplets, with direct implications for the encapsulation and controlled release of therapeutics for drug delivery applications. Ministry of Education (MOE) This research was funded by the Singapore Ministry of Education (MOE) through an Academic Research Fund (AcRF) Tier 3 grant (grant no. MOE 2019-T3-1-012). 2022-07-20T03:13:28Z 2022-07-20T03:13:28Z 2021 Journal Article Lim, J., Kumar, A., Low, K. J. Y., Verma, C. S., Mu, Y., Miserez, A. & Pervushin, K. (2021). Liquid-liquid phase separation of short histidine- and tyrosine-rich peptides: sequence specificity and molecular topology. Journal of Physical Chemistry B, 125(25), 6776-6790. https://dx.doi.org/10.1021/acs.jpcb.0c11476 1520-6106 https://hdl.handle.net/10356/160365 10.1021/acs.jpcb.0c11476 34106723 2-s2.0-85108662987 25 125 6776 6790 en MOE 2019-T3-1-012 Journal of Physical Chemistry B © 2021 American Chemical Society. All rights reserved. |
| spellingShingle | Engineering::Chemical engineering Aromatic Residues Proteins Lim, Jessica Kumar, Akshita Low, Kimberly Jia Yi Verma, Chandra Shekhar Mu, Yuguang Miserez, Ali Pervushin, Konstantin Liquid-liquid phase separation of short histidine- and tyrosine-rich peptides: sequence specificity and molecular topology |
| title | Liquid-liquid phase separation of short histidine- and tyrosine-rich peptides: sequence specificity and molecular topology |
| title_full | Liquid-liquid phase separation of short histidine- and tyrosine-rich peptides: sequence specificity and molecular topology |
| title_fullStr | Liquid-liquid phase separation of short histidine- and tyrosine-rich peptides: sequence specificity and molecular topology |
| title_full_unstemmed | Liquid-liquid phase separation of short histidine- and tyrosine-rich peptides: sequence specificity and molecular topology |
| title_short | Liquid-liquid phase separation of short histidine- and tyrosine-rich peptides: sequence specificity and molecular topology |
| title_sort | liquid liquid phase separation of short histidine and tyrosine rich peptides sequence specificity and molecular topology |
| topic | Engineering::Chemical engineering Aromatic Residues Proteins |
| url | https://hdl.handle.net/10356/160365 |
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