Self‐assembling Peptides with Internal Ionizable Unnatural Amino Acids: A General Approach to pH‐responsive Peptide Materials

Asokan‐Sheeja, Haritha; Yang, Su; Adones, Ashley A.; Chen, Weike; Fulton, Brandon B.; Chintapula, Uday K.; Nguyen, Kytai T.; Lovely, Carl J.; Brautigam, Chad A.; Nam, Kwangho; Dong, He

doi:10.1002/asia.202200724

Title: Self‐assembling Peptides with Internal Ionizable Unnatural Amino Acids: A General Approach to pH‐responsive Peptide Materials

Journal Article · Tue Oct 04 00:00:00 EDT 2022 · Chemistry - An Asian Journal

DOI:https://doi.org/10.1002/asia.202200724· OSTI ID:1885088

Asokan‐Sheeja, Haritha ^[1]; Yang, Su ^[1]; Adones, Ashley A. ^[1]; Chen, Weike ^[1]; Fulton, Brandon B. ^[1]; Chintapula, Uday K. ^[2]; Nguyen, Kytai T. ^[2]; Lovely, Carl J. ^[1]; Brautigam, Chad A. ^[3]; Nam, Kwangho ^[1];

^[1]

Department of Chemistry and Biochemistry The University of Texas at Arlington 701 S Nedderman Dr Arlington 76019 TX USA
Department of Bioengineering The University of Texas at Arlington 701 S Nedderman Dr 76019 TX Arlington USA
Department of Biophysics The University of Texas Southwestern Medical Center 5323 Harry Hines Blvd. 75390 TX Dallas USA

Abstract Self‐assembled peptides are an emerging family of biomaterials that show great promise for a range of biomedical and biotechnological applications. Introducing and tuning the pH‐responsiveness of the assembly is highly desirable for improving their biological activities. Inspired by proteins with internal ionizable residues, we report a simple but effective approach to constructing pH‐responsive peptide assembly containing unnatural ionic amino acids with an aliphatic tertiary amine side chain. Through a combined experimental and computational investigation, we demonstrate that these residues can be accommodated and stabilized within the internal hydrophobic compartment of the peptide assembly. The hydrophobic microenvironment shifts their pK _a significantly from a basic pH typically found for free amines to a more biologically relevant pH in the weakly acidic range. The pH‐induced ionization and ionization‐dependent self‐assembly and disassembly are thoroughly investigated and correlated with the biological activity of the assembly. This new approach has unique advantages in tuning the pH‐responsiveness of self‐assembled peptides across a large pH range in a complex biological environment. We anticipate the ionizable amino acids developed here can be widely applicable to the synthesis and self‐assembly of many amphiphilic peptides with endowed pH‐responsive properties to enhance their biological activities toward applications ranging from targeted therapeutic delivery to proton transport.

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Sponsoring Organization:: USDOE

OSTI ID:: 1885088

Journal Information:: Chemistry - An Asian Journal, Journal Name: Chemistry - An Asian Journal Vol. 17 Journal Issue: 19; ISSN 1861-4728

Publisher:: Wiley Blackwell (John Wiley & Sons)Copyright Statement

Country of Publication:: United Kingdom

Language:: English

References (60)

pH- and concentration-dependent supramolecular self-assembly of a naturally occurring octapeptide Ghosh, Goutam; Fernández, Gustavo Beilstein Journal of Organic Chemistry, Vol. 16 https://doi.org/10.3762/bjoc.16.168	journal	August 2020
pH-Responsive Biocompatible Supramolecular Peptide Hydrogel Ghosh, Goutam; Barman, Ranajit; Sarkar, Jayita The Journal of Physical Chemistry B, Vol. 123, Issue 27 https://doi.org/10.1021/acs.jpcb.9b02999	journal	June 2019
Self-assembly of peptide amphiphiles: From molecules to nanostructures to biomaterials Cui, Honggang; Webber, Matthew J.; Stupp, Samuel I. Biopolymers, Vol. 94, Issue 1, p. 1-18 https://doi.org/10.1002/bip.21328	journal	January 2010
Recent advances: peptides and self-assembled peptide-nanosystems for antimicrobial therapy and diagnosis Zou, Pengfei; Chen, Wen-Ting; Sun, Tongyi Biomaterials Science, Vol. 8, Issue 18 https://doi.org/10.1039/D0BM00789G	journal	January 2020
Self-Assembling Ability Determines the Activity of Enzyme-Instructed Self-Assembly for Inhibiting Cancer Cells Feng, Zhaoqianqi; Wang, Huaimin; Chen, Xiaoyi Journal of the American Chemical Society, Vol. 139, Issue 43 https://doi.org/10.1021/jacs.7b07147	journal	October 2017
Tunable, Ultrasensitive pH-Responsive Nanoparticles Targeting Specific Endocytic Organelles in Living Cells Zhou, Kejin; Wang, Yiguang; Huang, Xiaonan Angewandte Chemie International Edition, Vol. 50, Issue 27 https://doi.org/10.1002/anie.201100884	journal	April 2011
Minimalistic peptide supramolecular co-assembly: expanding the conformational space for nanotechnology Makam, Pandeeswar; Gazit, Ehud Chemical Society Reviews, Vol. 47, Issue 10 https://doi.org/10.1039/C7CS00827A	journal	January 2018
Molecular mechanisms of antibacterial and antitumor actions of designed surfactant-like peptides Chen, Cuixia; Hu, Jing; Zhang, Shengzhong Biomaterials, Vol. 33, Issue 2 https://doi.org/10.1016/j.biomaterials.2011.09.059	journal	January 2012
Protein-like Nanoparticles Based on Orthogonal Self-Assembly of Chimeric Peptides Jiang, Linhai; Xu, Dawei; Namitz, Kevin E. Small, Vol. 12, Issue 37 https://doi.org/10.1002/smll.201600910	journal	August 2016
Self-Assembled Peptide Nanofibers Display Natural Antimicrobial Peptides to Selectively Kill Bacteria without Compromising Cytocompatibility Chen, Weike; Yang, Su; Li, Shuxin ACS Applied Materials & Interfaces, Vol. 11, Issue 32 https://doi.org/10.1021/acsami.9b09583	journal	July 2019
Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes Ryckaert, Jean-Paul; Ciccotti, Giovanni; Berendsen, Herman J. C. Journal of Computational Physics, Vol. 23, Issue 3 https://doi.org/10.1016/0021-9991(77)90098-5	journal	March 1977
Designed filamentous cell penetrating peptides: probing supramolecular structure-dependent membrane activity and transfection efficiency Xu, Dawei; Dustin, Derek; Jiang, Linhai Chemical Communications, Vol. 51, Issue 59 https://doi.org/10.1039/C5CC02699G	journal	January 2015
Reorganization of hydrogen bond network makes strong polyelectrolyte brushes pH-responsive Wu, Bo; Wang, Xiaowen; Yang, Jun Science Advances, Vol. 2, Issue 8 https://doi.org/10.1126/sciadv.1600579	journal	August 2016
Organic Nanotube with Subnanometer, pH-Responsive Lumen Darnall, Shawn M.; Li, Changyi; Dunbar, Martha Journal of the American Chemical Society, Vol. 141, Issue 28 https://doi.org/10.1021/jacs.9b03732	journal	June 2019
pH-Responsive Self-Assembly of Designer Aromatic Peptide Amphiphiles and Enzymatic Post-Modification of Assembled Structures Wakabayashi, Rie; Higuchi, Ayato; Obayashi, Hiroki International Journal of Molecular Sciences, Vol. 22, Issue 7 https://doi.org/10.3390/ijms22073459	journal	March 2021
Comparison of simple potential functions for simulating liquid water Jorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D. The Journal of Chemical Physics, Vol. 79, Issue 2 https://doi.org/10.1063/1.445869	journal	July 1983
Stimuli-responsive self-assembling peptides made from antibacterial peptides Liu, Yanfei; Yang, Yanlian; Wang, Chen Nanoscale, Vol. 5, Issue 14 https://doi.org/10.1039/c3nr00225j	journal	January 2013
Control over Multiple Nano‐ and Secondary Structures in Peptide Self‐Assembly Ghosh, Goutam; Barman, Ranajit; Mukherjee, Anurag Angewandte Chemie International Edition, Vol. 61, Issue 5 https://doi.org/10.1002/anie.202113403	journal	December 2021
Self-assembly of cationic multidomain peptide hydrogels: supramolecular nanostructure and rheological properties dictate antimicrobial activity Jiang, Linhai; Xu, Dawei; Sellati, Timothy J. Nanoscale, Vol. 7, Issue 45 https://doi.org/10.1039/C5NR05233E	journal	January 2015
All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of Proteins ^† MacKerell, A. D.; Bashford, D.; Bellott, M. The Journal of Physical Chemistry B, Vol. 102, Issue 18 https://doi.org/10.1021/jp973084f	journal	April 1998
New faster CHARMM molecular dynamics engine Hynninen, Antti-Pekka; Crowley, Michael F. Journal of Computational Chemistry, Vol. 35, Issue 5 https://doi.org/10.1002/jcc.23501	journal	December 2013
CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields Vanommeslaeghe, K.; Hatcher, E.; Acharya, C. Journal of Computational Chemistry https://doi.org/10.1002/jcc.21367	journal	January 2009
Self-Assembling Behavior of pH-Responsive Peptide A6K without End-Capping Zhang, Peng; Wang, Fenghuan; Wang, Yuxuan Molecules, Vol. 25, Issue 9 https://doi.org/10.3390/molecules25092017	journal	April 2020
Supramolecular self-assembly of fluorescent peptide amphiphiles for accurate and reversible pH measurement Mei, Leixia; He, Suyun; Zhang, Li Organic & Biomolecular Chemistry, Vol. 17, Issue 4 https://doi.org/10.1039/C8OB02983K	journal	January 2019
pH‐Responsive Charge‐Conversion Progelator Peptides Carlini, Andrea S.; Choi, Wonmin; McCallum, Naneki C. Advanced Functional Materials, Vol. 31, Issue 13 https://doi.org/10.1002/adfm.202007733	journal	January 2021
Structurally Defined Nanoscale Sheets from Self-Assembly of Collagen-Mimetic Peptides Jiang, Tao; Xu, Chunfu; Liu, Yang Journal of the American Chemical Society, Vol. 136, Issue 11 https://doi.org/10.1021/ja412867z	journal	March 2014
Tuning carbohydrate density enhances protein binding and inhibition by glycosylated β-sheet peptide nanofibers Restuccia, Antonietta; Hudalla, Gregory A. Biomaterials Science, Vol. 6, Issue 9 https://doi.org/10.1039/C8BM00533H	journal	January 2018
Large shifts in pKa values of lysine residues buried inside a protein Isom, D. G.; Castaneda, C. A.; Cannon, B. R. Proceedings of the National Academy of Sciences, Vol. 108, Issue 13 https://doi.org/10.1073/pnas.1010750108	journal	March 2011
Self-Assembling Cages from Coiled-Coil Peptide Modules Fletcher, J. M.; Harniman, R. L.; Barnes, F. R. H. Science, Vol. 340, Issue 6132 https://doi.org/10.1126/science.1233936	journal	April 2013
Dual modes of antitumor action of an amphiphilic peptide A9K Xu, Hai; Chen, Cui Xia; Hu, Jing Biomaterials, Vol. 34, Issue 11 https://doi.org/10.1016/j.biomaterials.2012.12.039	journal	April 2013
Improved Treatment of the Protein Backbone in Empirical Force Fields MacKerell, Alexander D.; Feig, Michael; Brooks, Charles L. Journal of the American Chemical Society, Vol. 126, Issue 3 https://doi.org/10.1021/ja036959e	journal	January 2004
p H-Sensitive Liposomes: Possible Clinical Implications Yatvin, M. B.; Kreutz, W.; Horwitz, B. A. Science, Vol. 210, Issue 4475 https://doi.org/10.1126/science.7434025	journal	December 1980
pH‐Responsive Superwettability Surface: The Study of Oil Dewetting Ability from Air to Water on a Rough Surface and Selective Oil‐Water Separation Tang, Lei; Zeng, Zhixiang; Wang, Gang Advanced Materials Interfaces, Vol. 7, Issue 22 https://doi.org/10.1002/admi.202001147	journal	September 2020
Paclitaxel-loaded pH responsive hydrogel based on self-assembled peptides for tumor targeting Raza, Faisal; Zhu, Ying; Chen, Li Biomaterials Science, Vol. 7, Issue 5 https://doi.org/10.1039/C9BM00139E	journal	January 2019
Defining the Landscape of the Pauling-Corey Rippled Sheet: An Orphaned Motif Finding New Homes Raskatov, Jevgenij A.; Schneider, Joel P.; Nilsson, Bradley L. Accounts of Chemical Research, Vol. 54, Issue 10 https://doi.org/10.1021/acs.accounts.1c00084	journal	April 2021
Fabrication and Microscopic and Spectroscopic Characterization of Cytocompatible Self-Assembling Antimicrobial Nanofibers Xu, Dawei; Chen, Weike; Tobin-Miyaji, Yuto J. ACS Infectious Diseases, Vol. 4, Issue 9 https://doi.org/10.1021/acsinfecdis.8b00069	journal	June 2018
Structure of a fibronectin type III domain from tenascin phased by MAD analysis of the selenomethionyl protein Leahy, D.; Hendrickson, W.; Aukhil, I. Science, Vol. 258, Issue 5084 https://doi.org/10.1126/science.1279805	journal	November 1992
Modular design and self-assembly of multidomain peptides towards cytocompatible supramolecular cell penetrating nanofibers Yang, Su; Dong, He RSC Advances, Vol. 10, Issue 49 https://doi.org/10.1039/D0RA04748A	journal	January 2020
Antimicrobial properties of enzymatically triggered self-assembling aromatic peptide amphiphiles Hughes, Meghan; Debnath, Sisir; Knapp, Charles W. Biomaterials Science, Vol. 1, Issue 11 https://doi.org/10.1039/c3bm60135h	journal	January 2013
Hydrazone linkages in pH responsive drug delivery systems Sonawane, Sandeep J.; Kalhapure, Rahul S.; Govender, Thirumala European Journal of Pharmaceutical Sciences, Vol. 99 https://doi.org/10.1016/j.ejps.2016.12.011	journal	March 2017
Optimization of the Additive CHARMM All-Atom Protein Force Field Targeting Improved Sampling of the Backbone ϕ, ψ and Side-Chain χ ₁ and χ ₂ Dihedral Angles Best, Robert B.; Zhu, Xiao; Shim, Jihyun Journal of Chemical Theory and Computation, Vol. 8, Issue 9 https://doi.org/10.1021/ct300400x	journal	August 2012
Ionic Liquid‐Based Stimuli‐Responsive Functional Materials Cui, Jiecheng; Li, Yi; Chen, Dong Advanced Functional Materials, Vol. 30, Issue 50 https://doi.org/10.1002/adfm.202005522	journal	September 2020
Nucleation and Growth of Amino Acid and Peptide Supramolecular Polymers through Liquid-Liquid Phase Separation Yuan, Chengqian; Levin, Aviad; Chen, Wei Angewandte Chemie International Edition, Vol. 58, Issue 50 https://doi.org/10.1002/anie.201911782	journal	November 2019
Hierarchically oriented organization in supramolecular peptide crystals Yuan, Chengqian; Ji, Wei; Xing, Ruirui Nature Reviews Chemistry, Vol. 3, Issue 10 https://doi.org/10.1038/s41570-019-0129-8	journal	September 2019
Multicomponent peptide assemblies Raymond, Danielle M.; Nilsson, Bradley L. Chemical Society Reviews, Vol. 47, Issue 10 https://doi.org/10.1039/C8CS00115D	journal	January 2018
Arginine residues at internal positions in a protein are always charged Harms, M. J.; Schlessman, J. L.; Sue, G. R. Proceedings of the National Academy of Sciences, Vol. 108, Issue 47 https://doi.org/10.1073/pnas.1104808108	journal	November 2011
Chirality-selected phase behaviour in ionic polypeptide complexes Perry, Sarah L.; Leon, Lorraine; Hoffmann, Kyle Q. Nature Communications, Vol. 6, Issue 1 https://doi.org/10.1038/ncomms7052	journal	January 2015
Supramolecular Nanostructures Formed by Anticancer Drug Assembly Cheetham, Andrew G.; Zhang, Pengcheng; Lin, Yi-an Journal of the American Chemical Society, Vol. 135, Issue 8 https://doi.org/10.1021/ja3115983	journal	February 2013
Canonical dynamics: Equilibrium phase-space distributions Hoover, William G. Physical Review A, Vol. 31, Issue 3 https://doi.org/10.1103/PhysRevA.31.1695	journal	March 1985
pH-Responsive polymers Kocak, G.; Tuncer, C.; Bütün, V. Polymer Chemistry, Vol. 8, Issue 1 https://doi.org/10.1039/C6PY01872F	journal	January 2017
pH-responsive branched peptide amphiphile hydrogel designed for applications in regenerative medicine with potential as injectable tissue scaffolds Lin, Brian F.; Megley, Katie A.; Viswanathan, Nickesh Journal of Materials Chemistry, Vol. 22, Issue 37 https://doi.org/10.1039/c2jm31745a	journal	January 2012
Role of Hydrophobic Clusters in the Stability of α-Helical Coiled Coils and Their Conversion to Amyloid-like β-Sheets Dong, He; Hartgerink, Jeffrey D. Biomacromolecules, Vol. 8, Issue 2 https://doi.org/10.1021/bm060871m	journal	February 2007
Bacterial acidity-triggered antimicrobial activity of self-assembling peptide nanofibers Chen, Weike; Li, Shuxin; Renick, Paul Journal of Materials Chemistry B, Vol. 7, Issue 18 https://doi.org/10.1039/C9TB00134D	journal	January 2019
pH-Responsive Self-Assemblies from the Designed Folic Acid-Modified Peptide Drug for Dual-Targeting Delivery Wang, Dong; Fan, Zhihao; Zhang, Xuecheng Langmuir, Vol. 37, Issue 1 https://doi.org/10.1021/acs.langmuir.0c02930	journal	December 2020
Self-Assembly of Multidomain Peptides: Balancing Molecular Frustration Controls Conformation and Nanostructure Dong, He; Paramonov, Sergey E.; Aulisa, Lorenzo Journal of the American Chemical Society, Vol. 129, Issue 41 https://doi.org/10.1021/ja072536r	journal	October 2007
pH-Responsive Peptide Supramolecular Hydrogels with Antibacterial Activity Wan, Yaoming; Liu, Libing; Yuan, Shuaishuai Langmuir, Vol. 33, Issue 13 https://doi.org/10.1021/acs.langmuir.6b03986	journal	March 2017
pH-Responsive Polymers as Gene Carriers Park, In-Kyu; Singha, Kaushik; Arote, Rohidas B. Macromolecular Rapid Communications, Vol. 31, Issue 13 https://doi.org/10.1002/marc.200900867	journal	May 2010
Self-assembled peptide fibrils with pH-sensitive reversible surface-active properties Dao, Huy Minh; Parajuli, Sanjiv; Urena-Benavides, Esteban Colloid and Interface Science Communications, Vol. 39 https://doi.org/10.1016/j.colcom.2020.100325	journal	November 2020
Mechanism of the pH-Controlled Self-Assembly of Nanofibers from Peptide Amphiphiles Cote, Yoann; Fu, Iris W.; Dobson, Eric T. The Journal of Physical Chemistry C, Vol. 118, Issue 29 https://doi.org/10.1021/jp5048024	journal	July 2014
A summary of the measured p K values of the ionizable groups in folded proteins Grimsley, Gerald R.; Scholtz, J. Martin; Pace, C. Nick Protein Science https://doi.org/10.1002/pro.19	journal	January 2008

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