Research Overview

Peptide Self-Assembly: From Dysfunction to Function

     The self-assembly of peptides and proteins into cross-beta amyloid structures is a defining characteristic of amyloid pathologies including Alzheimer’s disease, Parkinson’s disease, type 2 diabetes, and prion encephalopathies. Amyloid protein assemblies are not limited to pathological conditions, but also exist as evolutionarily conserved motifs with defined biological function. There is growing interest in exploiting peptide self-assembly phenomena for the development of novel functional structures with applications in biomedicine, energy, and materials. The Nilsson group is focused on understanding the noncovalent interactions that drive peptide self-assembly in order to facilitate novel approaches to perturb and control these processes and to exploit these interactions to enable new strategies for the noncovalent synthesis of functional and dynamic self-assembled materials. These efforts include:

1) The characterization of the physicochemical parameters that give rise to protein aggregation and fibril formation, with a focus on the Alzheimer’s disease amyloid-beta peptide and HIV SEVI amyloid.

2) The development of materials derived from self-assembling peptides for use as scaffolds for tissue engineering, as anti-HIV microbicides, and other applications.

3) The development of low molecular weight phenylalanine derivatives that undergo self-assembly and hydrogelation to provide a range of supramolecular materials that are cost-effective alternatives to higher molecular weight peptides.

4) The development of cyclic amphipathic peptides for the in vivo delivery of therapeutic oligonucleotides.    

Research Interests

• Peptide self-assembly
• amyloid peptides
• amyloid-inspired materials
• bioorganic chemistry
• supramolecular chemistry

Selected Publications

• Investigating the Effects of Peptoid Substitutions in Self-Assembly of Fmoc-Diphenylalanine Derivatives. Annada Rajbhandary and Bradley L. Nilsson. Biopolymers (Peptide Science) 2016, 106, Accepted. DOI: 10.1002/bip.22994.
• Amyloid-Inspired Optical Waveguides from Multicomponent Crystalline Microtubes. Wathsala Liyanage, Nicole M. B. Cogan, and Bradley L. Nilsson. ChemNanoMat 2016, 2, 800–804. DOI: 10.1002/cnma.201600123.
• Functional Delivery of siRNA by Disulfide-Constrained Cyclic Amphipathic Peptides. Jade J. Welch, Ria J. Swanekamp, Christiaan King, David A. Dean, Bradley L. Nilsson. ACS Medicinal Chemistry Letters 2016, 7, 584–589. DOI: 10.1021/acsmedchemlett.6b00031.
• Substituent Effects on the Self-Assembly/Coassembly and Hydrogelation of Phenylalanine Derivatives. Wathsala Liyanage, Bradley L. Nilsson. Langmuir 2016, 32, 787–799. DOI: 10.1021/acs.langmuir.5b03227.
• Mechanisms of Tau and Abeta-induced Excitotoxicity. Susanne P. Pallo, John DiMaio, Alexis Cook, Bradley Nilsson, Gail V. W. Johnson. Brain Research 2016, 1634, 119–131. DOI: 10.1016/j.brainres.2015.12.048.
• Spontaneous Transition of Self-Assembled Hydrogel Fibrils into Crystalline Microtubes Enables a Rational Strategy to Stabilize the Hydrogel State. Wathsala Liyanage, William W. Brennessel, Bradley L. Nilsson. Langmuir 2015, 31, 9933–9942. DOI: 10.1021/acs.langmuir.5b01953.
• Swanekamp, R.J., Welch, J.J., Nilsson, B.L. "Proteolytic Stability of Amphipathic Peptide Hydrogels Composed of Self-Assembled Pleated β-Sheet or Coassembled Rippled β-Sheet Fibrils," Chemical Communications 2014, DOI: http://dx.doi.org/10.1039/C4CC04644G.
• Multicomponent Dipeptide Hydrogels as Extracellular Matrix-Mimetic Scaffolds for Cell Culture Applications. Wathsala Liyanage, Kanika Vats, Annada Rajbhandary, Danielle S. W. Benoit, Bradley L. Nilsson. Chemical Communications 2015, 51, 11260–11263. DOI: 10.1039/C5CC03162A.
• Cogan, N.M.B., Bowerman, C.J., Nogaj, L.J., Nilsson, B.L., Krauss, T.D. "Selective Suspension of Single-Walled Carbon Nanotubes using &$#946;-Sheet Polypeptides," Journal of Physical Chemistry C 2014, 118, 5935-5944, DOI: http://dx.doi.org/10.1021/jp410870y
• Doran, T.M., Ryan, D.M., Nilsson, B.L. "Reversible Photocontrol of Self-Assembled Peptide Hydrogel Viscoelasticity," Polymer Chemistry 2014, 5, 241-248, DOI: http://dx.doi.org/10.1039/C3PY00903C
• Lee, N.R., Bowerman, C.J., Nilsson, B.L. "Effects of Varied Sequence Pattern on the Self-Assembly of Amphipathic Peptides," Biomacromolecules 2013, 14, 3267-3277, DOI: http://dx.doi.org/10.1021/bm400876s
• Lee, N.R., Bowerman, C.J., Nilsson, B.L. "Sequence Length Determinants for Self-Assembly of Amphipathic β-Cheet Peptides," Biopolymers (Peptide Science) 2013, 100, 738-750, DOI: http://dx.doi.org/10.1002/bip.22248
• Easterhoff, D., DiMaio, J.T.M., Liyanage, W., Lo, C., Bae, W., Doran, T.M., Smrcka, A., Nilsson, B.L., Dewhurst, S. "Fluorescence Detection of Cationic Amyloid Fibrils in Human Semen," Bioorganic and Medicinal Chemistry Letters 2013, 23, 5199-5202, DOI: http://dx.doi.org/10.1016/j.bmcl.2013.06.097
• Swanekamp, R.J., DiMaio, J.T.M., Bowerman, C.J., Nilsson, B.L. "Coassembly of Enantiomeric Amphipathic Peptides into Amyloid-Inspired Rippled β-Sheet Fibrils," J. Am. Chem. Soc. 2012, 134, 5556-5559.
• Bowerman, C.J., Nilsson, B.L. "Self-Assembly of Amphipathic β-Sheet Peptides: Insights and Applications," Biopolymers 2012, 98, 169-184.
• Olsen, J. S., DiMaio, J. T. M., Doran, T. M., Brown, C., Nilsson, B.L., Dewhurst, S. "Seminal plasma accelerates SEVI fibril formation by the PAP[248-286] peptide," J. Biol. Chem. 2012, 287, 11842-11849.
• Doran, T. M., Anderson, E. A., Latchney, S. E., Opanashuk, L. A., Nilsson, B.L. "Turn Nucleation Perturbs Amyloid-β Self-Assembly and Cytotoxicity," J. Mol. Biol. 2012, 421, 315-328.
• Doran, T. M., Anderson, E. A., Latchney, S. E., Opanashuk, L. A., Nilsson, B.L. "An Azobenzene Photoswitch Sheds Light on Turn Nucleation in Amyloid-β Self-Assembly," ACS Chem. Neurosci. 2012, 3, 211-220.
• Doran, T. M., Kamens, A. J., Byrnes, N. K., Nilsson, B.L. "Role of Amino Acid Hydrophobicity, Aromaticity and Molecular Volume on IAPP(20–29) Amyloid Self-Assembly," Proteins 2012, 80, 1053-1065.
• Ryan, D. M., Nilsson, B.L. "Self-Assembled Amino Acids and Dipeptides as Noncovalent Hydrogels for Tissue Engineering," Polym. Chem. 2012, 3, 18-33.
• Ryan, D. M., Doran, T. M., Nilsson, B.L. "Complementary π-π Interactions Induce Multi-Component Coassembly into Functional Fibrils," Langmuir 2011, 27, 11145-11156.
• Bowerman, C. J., Liyanage, W., Federation, A. J., Nilsson, B.L. "Tuning β-Sheet Peptide Self-Assembly and Hydrogelation Behavior by Modification of Sequence Hydrophobicity and Aromaticity," Biomacromolecules 2011, 12, 2735-2745.
• Ryan, D.M., Doran, T.M., Anderson, S.B., Nilsson, B.L. "The Effect of C-Terminal Modification on the Self-Assembly and Hydrogelation of Fluorinated Fmoc-Phe Derivatives," Langmuir 2011, 27, 4029-4039.
• Easterhoff, D., DiMaio, J.T.M., Doran, T.M., Dewhurst, S., Nilsson, B.L. "Enhancement of HIV-1 Infectivity by Simple, Self-Assembling Modular Peptides," Biophysical Journal 2011, 100, 1325-1334.
• Ryan, D.M., Doran, T.M., Nilsson, B.L. "Stabilizing Self-Assembled Fmoc-F5-Phe Hydrogels by Co-Assembly with PEG-Functionalized Monomers," Chemical Communications 2011, 47, 475-477.
• Senguen, F.T., Doran, T.M., Anderson, E.A., Nilsson, B.L. "Clarifying the Influence of Core Amino Acid Hydrophobicity, Secondary Structure Propensity, and Molecular Volume on Amyloid-β 16–22 Self-Assembly," Molecular BioSystems 2011, 7, 497-510.
• Senguen, F.T., Lee, N.R., Gu, X., Ryan, D.M., Doran, T.M., Anderson, E.A., Nilsson, B.L. "Probing aromatic, hydrophobic, and steric effects on the self-assembly of an amyloid-β fragment peptide," Molecular BioSystems 2011, 7, 486-496.
• Olsen, J.S., Brown, C., Capule, C.C., Rubinshtein, M., Doran, T.M., Srivastava, R.K., Feng, C., Nilsson, B.L., Yang, J., Dewhurst, S. "Amyloid Binding Small Molecules Efficiently Block SEVI and Semen Mediated Enhancement of HIV-1 Infection," Journal of Biological Chemistry 2010, 285, 35488-35496.
• Bowerman, C.J., Nilsson, B.L. "A Reductive Trigger for Peptide Self-Assembly and Hydrogelation," Journal of the American Chemical Society 2010, 132, 9526-9527.
• Ryan, D.M., Anderson, S.B., Nilsson, B.L. "The Influence of Side-Chain Halogenation on the Self-Assembly and Hydrogelation of Fmoc-Phenylalanine Derivatives," Soft Matter 2010, 6, 3220-3231.
• Ryan, D.M., Anderson, S.B., Senguen, F.T., Youngman, R.E., Nilsson, B.L. "Self-assembly and hydrogelation promoted by F5-phenylalanine," Soft Matter 2010, 6, 475-479.
• Bowerman, C.J., Ryan, D.M., Nissan, D.A., Nilsson, B.L. "The effect of increasing hydrophobicity on the self-assembly of amphipathic β-sheet peptides," Molecular BioSystems 2009, 5, 1058-1069.