Fernando Teran Arce
- Research Associate Professor, Medicine
- Research Associate Professor
- M.S. Physics
- Technical University of Munich, Munich, Germany
- Scanning Tunneling Microscopy and Electrochemical Methods for Prospective in situ Imaging of Biological Samples
- Ph.D. Physics
- National University of La Plata, Argentina, La Plata, Argentina
- Scanning Probe Microscopy Applied to the Study of the Molecular Structure and Surface Dynamics of Organic Monolayers
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DissertationBME 920 (Spring 2021)
DissertationBME 920 (Fall 2020)
DissertationBME 920 (Spring 2020)
ResearchBME 900 (Fall 2019)
ResearchBME 900 (Spring 2019)
Master's ReportBME 909 (Fall 2018)
Rsrch Meth Biomed EngrBME 597G (Fall 2018)
- Younger, S., Jang, H., Davies, H. A., Niemiec, M. J., Garcia, J. G., Nussinov, R., Migrino, R., Madine, J., & Teran Arce, P. F. (2019). Medin Oligomer Membrane Pore Formation: A Potential Mechanism of Vascular Dysfunction. Biophysical Journal.More infoMedin, a 50-amino-acid cleavage product of the milk fat globule-EGF factor 8 protein, is one of the most common forms of localized amyloid found in the vasculature of individuals older than 50 years. Medin induces endothelial dysfunction and vascular inflammation, yet despite its prevalence in the human aorta and multiple arterial beds, little is known about the nature of its pathology. Medin oligomers have been implicated in the pathology of aortic aneurysm, aortic dissection, and more recently, vascular dementia. Recent in vitro biomechanical measurements found increased oligomer levels in aneurysm patients with altered aortic wall integrity. Our results suggest an oligomer-mediated toxicity mechanism for medin pathology. Using lipid bilayer electrophysiology, we show that medin oligomers induce ionic membrane permeability by pore formation. Pore activity was primarily observed for preaggregated medin species from the growth-phase and rarely for lag-phase species. Atomic force microscopy (AFM) imaging of medin aggregates at different stages of aggregation revealed the gradual formation of flat domains resembling the morphology of supported lipid bilayers. Transmission electron microscopy images showed the coexistence of compact oligomers, largely consistent with the AFM data, and larger protofibrillar structures. Circular dichroism spectroscopy revealed the presence of largely disordered species and suggested the presence of β-sheets. This observation and the significantly lower thioflavin T fluorescence emitted by medin aggregates compared to amyloid-β fibrils, along with the absence of amyloid fibers in the AFM and transmission electron microscopy images, suggest that medin aggregation into pores follows a nonamyloidogenic pathway. In silico modeling by molecular dynamics simulations provides atomic-level structural detail of medin pores with the CNpNC barrel topology and diameters comparable to values estimated from experimental pore conductances.
- Ramachandran, S., Teran Arce, F., & Lal, R. (2018). Potential role of atomic force microscopy in systems biology. Wiley interdisciplinary reviews. Systems biology and medicine, 3(6), 702-16.More infoSystems biology is a quantitative approach for understanding a biological system at its global level through systematic perturbation and integrated analysis of all its components. Simultaneous acquisition of information data sets pertaining to the system components (e.g., genome, proteome) is essential to implement this approach. There are limitations to such an approach in measuring gene expression levels and accounting for all proteins in the system. The success of genomic studies is critically dependent on polymerase chain reaction (PCR) for its amplification, but PCR is very uneven in amplifying the samples, ineffective in scarce samples and unreliable in low copy number transcripts. On the other hand, lack of amplifying techniques for proteins critically limits their identification to only a small fraction of high concentration proteins. Atomic force microscopy (AFM), AFM cantilever sensors, and AFM force spectroscopy in particular, could address these issues directly. In this article, we reviewed and assessed their potential role in systems biology.
- Huang, Q., Lee, J., Arce, F. T., Yoon, I., Angsantikul, P., Liu, J., Shi, Y., Villanueva, J., Thamphiwatana, S., Ma, X., Zhang, L., Chen, S., Lal, R., & Sirbuly, D. J. (2017). Nanofibre optic force transducers with sub-piconewton resolution via near-field plasmon-dielectric interactions. NATURE PHOTONICS, 11(6), 352-+.
- Martinez Hernandez, A., Urbanke, H., Gillman, A. L., Lee, J., Ryazanov, S., Agbemenyah, H. Y., Benito, E., Jain, G., Kaurani, L., Grigorian, G., Leonov, A., Rezaei-Ghaleh, N., Wilken, P., Arce, F. T., Wagner, J., Fuhrman, M., Caruana, M., Camilleri, A., Vassallo, N., , Zweckstetter, M., et al. (2017). The diphenylpyrazole compound anle138b blocks Aβ channels and rescues disease phenotypes in a mouse model for amyloid pathology. EMBO molecular medicine.More infoAlzheimer's disease is a devastating neurodegenerative disease eventually leading to dementia. An effective treatment does not yet exist. Here we show that oral application of the compound anle138b restores hippocampal synaptic and transcriptional plasticity as well as spatial memory in a mouse model for Alzheimer's disease, when given orally before or after the onset of pathology. At the mechanistic level, we provide evidence that anle138b blocks the activity of conducting Aβ pores without changing the membrane embedded Aβ-oligomer structure. In conclusion, our data suggest that anle138b is a novel and promising compound to treat AD-related pathology that should be investigated further.
- Huang, Q., Arce, F. T., Lee, J., Yoon, I., Villanueva, J., Lal, R., & Sirbuly, D. J. (2016). Gap controlled plasmon-dielectric coupling effects investigated with single nanoparticle-terminated atomic force microscope probes. NANOSCALE, 8(39), 17102-17107.
- Jang, H., Arce, F. T., Lee, J., Gillman, A. L., Ramachandran, S., Kagan, B. L., Lal, R., & Nussinov, R. (2016). Computational Methods for Structural and Functional Studies of Alzheimer's Amyloid Ion Channels. Methods in molecular biology (Clifton, N.J.), 1345, 251-68.More infoAggregation can be studied by a range of methods, experimental and computational. Aggregates form in solution, across solid surfaces, and on and in the membrane, where they may assemble into unregulated leaking ion channels. Experimental probes of ion channel conformations and dynamics are challenging. Atomistic molecular dynamics (MD) simulations are capable of providing insight into structural details of amyloid ion channels in the membrane at a resolution not achievable experimentally. Since data suggest that late stage Alzheimer's disease involves formation of toxic ion channels, MD simulations have been used aiming to gain insight into the channel shapes, morphologies, pore dimensions, conformational heterogeneity, and activity. These can be exploited for drug discovery. Here we describe computational methods to model amyloid ion channels containing the β-sheet motif at atomic scale and to calculate toxic pore activity in the membrane.
- Santacruz-Gomez, K., Silva-Campa, E., Melendrez-Amavizca, R., Arce, F. T., Mata-Haro, V., Landon, P. B., Zhang, C., Pedroza-Montero, M., & Lal, R. (2016). Carboxylated nanodiamonds inhibit gamma-irradiation damage of human red blood cells. NANOSCALE, 8(13), 7189-7196.More infoNanodiamonds when carboxylated (cNDs) act as reducing agents and hence could limit oxidativedamage in biological systems. Gamma (γ)-irradiation of whole blood or its components is required inimmunocompetent patients to prevent transfusion-associated graft versus host disease (TA-GVHD).However, γ-irradiation of blood also deoxygenates red blood cells (RBCs) and induces oxidative damage,including abnormalities in cellular membranes and hemolysis. Using atomic force microscopy (AFM) andRaman spectroscopy, we examined the effect of cNDs on γ-irradiation mediated deoxygenation and morphologicaldamage of RBCs. γ-Radiation induced several morphological phenotypes, including stomatocytes,codocytes and echinocytes. While stomatocytes and codocytes are reversibly damaged RBCs,echinocytes are irreversibly damaged. AFM images show significantly fewer echinocytes among cNDtreatedγ-irradiated RBCs. The Raman spectra of γ-irradiated RBCs had more oxygenated hemoglobinpatterns when cND-treated, resembling those of normal, non-irradiated RBCs, compared to the noncND-treated RBCs. cND inhibited hemoglobin deoxygenation and morphological damage, possibly byneutralizing the free radicals generated during γ-irradiation. Thus cNDs have the therapeutic potential topreserve the quality of stored blood following γ-irradiation.
- Ramachandran, S., Teran Arce, F., & Lal, R. (2015). Potential role of atomic force microscopy in systems biology. Wiley interdisciplinary reviews. Systems biology and medicine, 3(6), 702-16.More infoSystems biology is a quantitative approach for understanding a biological system at its global level through systematic perturbation and integrated analysis of all its components. Simultaneous acquisition of information data sets pertaining to the system components (e.g., genome, proteome) is essential to implement this approach. There are limitations to such an approach in measuring gene expression levels and accounting for all proteins in the system. The success of genomic studies is critically dependent on polymerase chain reaction (PCR) for its amplification, but PCR is very uneven in amplifying the samples, ineffective in scarce samples and unreliable in low copy number transcripts. On the other hand, lack of amplifying techniques for proteins critically limits their identification to only a small fraction of high concentration proteins. Atomic force microscopy (AFM), AFM cantilever sensors, and AFM force spectroscopy in particular, could address these issues directly. In this article, we reviewed and assessed their potential role in systems biology.
- Gillman, A. L., Jang, H., Lee, J., Ramachandran, S., Kagan, B. L., Nussinov, R., & Arce, F. T. (2014). Activity and Architecture of Pyroglutamate-Modified Amyloid-beta (A beta(pE3-42)) Pores. JOURNAL OF PHYSICAL CHEMISTRY B, 118(26), 7335-7344.
- Gillman, A. L., Jang, H., Lee, J., Ramachandran, S., Kagan, B. L., Nussinov, R., & Teran Arce, F. (2014). Activity and architecture of pyroglutamate-modified amyloid-β (AβpE3-42) pores. The journal of physical chemistry. B, 118(26), 7335-44.More infoAmong the family of Aβ peptides, pyroglutamate-modified Aβ (AβpE) peptides are particularly associated with cytotoxicity in Alzheimer's disease (AD). They represent the dominant fraction of Aβ oligomers in the brains of AD patients, but their accumulation in the brains of elderly individuals with normal cognition is significantly lower. Accumulation of AβpE plaques precedes the formation of plaques of full-length Aβ (Aβ1-40/42). Most of these properties appear to be associated with the higher hydrophobicity of AβpE as well as an increased resistance to enzymatic degradation. However, the important question of whether AβpE peptides induce pore activity in lipid membranes and their potential toxicity compared with other Aβ pores is still open. Here we examine the activity of AβpE pores in anionic membranes using planar bilayer electrical recording and provide their structures using molecular dynamics simulations. We find that AβpE pores spontaneously induce ionic current across the membrane and have some similar properties to the other previously studied pores of the Aβ family. However, there are also some significant differences. The onset of AβpE3-42 pore activity is generally delayed compared with Aβ1-42 pores. However, once formed, AβpE3-42 pores produce increased ion permeability of the membrane, as indicated by a greater occurrence of higher conductance electrical events. Structurally, the lactam ring of AβpE peptides induces a change in the conformation of the N-terminal strands of the AβpE3-42 pores. While the N-termini of wild-type Aβ1-42 peptides normally reside in the bulk water region, the N-termini of AβpE3-42 peptides tend to reside in the hydrophobic lipid core. These studies provide a first step to an understanding of the enhanced toxicity attributed to AβpE peptides.
- Jang, H., Arce, F. T., Ramachandran, S., Kagan, B. L., Lal, R., & Nussinov, R. (2014). Disordered amyloidogenic peptides may insert into the membrane and assemble into common cyclic structural motifs. CHEMICAL SOCIETY REVIEWS, 43(19), 6750-6764.
- Lee, J., Gillman, A. L., Jang, H., Ramachandran, S., Kagan, B. L., Nussinov, R., & Arce, F. T. (2014). Role of the Fast Kinetics of Pyroglutamate-Modified Amyloid-beta Oligomers in Membrane Binding and Membrane Permeability. BIOCHEMISTRY, 53(28), 4704-4714.
- Lee, J., Gillman, A. L., Jang, H., Ramachandran, S., Kagan, B. L., Nussinov, R., & Teran Arce, F. (2014). Role of the fast kinetics of pyroglutamate-modified amyloid-β oligomers in membrane binding and membrane permeability. Biochemistry, 53(28), 4704-14.More infoMembrane permeability to ions and small molecules is believed to be a critical step in the pathology of Alzheimer's disease (AD). Interactions of oligomers formed by amyloid-β (Aβ) peptides with the plasma cell membrane are believed to play a fundamental role in the processes leading to membrane permeability. Among the family of Aβs, pyroglutamate (pE)-modified Aβ peptides constitute the most abundant oligomeric species in the brains of AD patients. Although membrane permeability mechanisms have been studied for full-length Aβ1-40/42 peptides, these have not been sufficiently characterized for the more abundant AβpE3-42 fragment. Here we have compared the adsorbed and membrane-inserted oligomeric species of AβpE3-42 and Aβ1-42 peptides. We find lower concentrations and larger dimensions for both species of membrane-associated AβpE3-42 oligomers. The larger dimensions are attributed to the faster self-assembly kinetics of AβpE3-42, and the lower concentrations are attributed to weaker interactions with zwitterionic lipid headgroups. While adsorbed oligomers produced little or no significant membrane structural damage, increased membrane permeabilization to ionic species is understood in terms of enlarged membrane-inserted oligomers. Membrane-inserted AβpE3-42 oligomers were also found to modify the mechanical properties of the membrane. Taken together, our results suggest that membrane-inserted oligomers are the primary species responsible for membrane permeability.
- Meckes, B., Ambrosi, C., Barnard, H., Arce, F. T., Sosinsky, G. E., & Lal, R. (2014). Atomic force microscopy shows connexin26 hemichannel clustering in purified membrane fragments. Biochemistry, 53(47), 7407-14.More infoConnexin proteins form hexameric assemblies known as hemichannels. When docked to form gap junction (GJ) channels, hemichannels play a critical role in cell-cell communication and cellular homeostasis, but often are functional entities on their own in unapposed cell membranes. Defects in the Connexin26 (Cx26) gene are the major cause of hereditary deafness arising from dysfunctional hemichannels in the cochlea. Structural studies of Cx26 hemichannels properly trafficked and inserted in plasma membranes, including their clustering that forms a plaque-like feature in whole gap junctions, are limited. We used atomic force microscopy (AFM) to study the surface topography of Cx26 hemichannels using two different membrane preparations. Rat Cx26 containing appended carboxy terminal V5 and hexahistidine tags were expressed in baculovirus/Sf9 cell systems. The expressed Cx26 proteins form hemichannels in situ in Sf9 cells that were then purified either as (1) Sf9 membrane fragments containing Cx26 hemichannels or (2) solubilized hemichannels. The latter were subsequently reconstituted in liposomes. AFM images of purified membrane fragments showed clusters of protein macromolecular structures in the membrane that at higher magnification corresponded to Cx26 hemichannels. Hemichannels reconstituted into DOPC bilayers displayed two populations of channel heights likely resulting from differences in orientations of inserted hemichannels. Hemichannels in the protein rich portions of purified membranes also showed a reduced channel height above the bilayer compared to membranes with reconstituted hemichannels perhaps due to reduced AFM probe access to the lipid bilayer. These preparations of purified membranes enriched for connexin hemichannels that have been properly trafficked and inserted in membranes provide a platform for high-resolution AFM imaging of the structure, interconnexon interactions, and cooperativity of properly trafficked and inserted noncrystalline connexin hemichannels.
- Meckes, B., Arce, F. T., Connelly, L. S., & Lal, R. (2014). Insulated Conducting Cantilevered Nanotips and Two-Chamber Recording System for High Resolution Ion Sensing AFM. SCIENTIFIC REPORTS, 4.
- Meckes, B., Arce, F. T., Connelly, L. S., & Lal, R. (2014). Insulated conducting cantilevered nanotips and two-chamber recording system for high resolution ion sensing AFM. Scientific reports, 4, 4454.More infoBiological membranes contain ion channels, which are nanoscale pores allowing controlled ionic transport and mediating key biological functions underlying normal/abnormal living. Synthetic membranes with defined pores are being developed to control various processes, including filtration of pollutants, charge transport for energy storage, and separation of fluids and molecules. Although ionic transport (currents) can be measured with single channel resolution, imaging their structure and ionic currents simultaneously is difficult. Atomic force microscopy enables high resolution imaging of nanoscale structures and can be modified to measure ionic currents simultaneously. Moreover, the ionic currents can also be used to image structures. A simple method for fabricating conducting AFM cantilevers to image pore structures at high resolution is reported. Tungsten microwires with nanoscale tips are insulated except at the apex. This allows simultaneous imaging via cantilever deflections in normal AFM force feedback mode as well as measuring localized ionic currents. These novel probes measure ionic currents as small as picoampere while providing nanoscale spatial resolution surface topography and is suitable for measuring ionic currents and conductance of biological ion channels.
- Meckes, B., Arnbrosi, C., Barnard, H., Arce, F. T., Sosinsky, G. E., & Lal, R. (2014). Atomic Force Microscopy Shows Connexin26 Hemichannel Clustering in Purified Membrane Fragments. BIOCHEMISTRY, 53(47), 7407-7414.
- Ramachandran, S., Arce, F. T., Patel, N. R., Quist, A. P., Cohen, D. A., & Lal, R. (2014). Structure and permeability of ion-channels by integrated AFM and waveguide TIRF microscopy. Scientific reports, 4, 4424.More infoMembrane ion channels regulate key cellular functions and their activity is dependent on their 3D structure. Atomic force microscopy (AFM) images 3D structure of membrane channels placed on a solid substrate. Solid substrate prevents molecular transport through ion channels thus hindering any direct structure-function relationship analysis. Here we designed a ~70 nm nanopore to suspend a membrane, allowing fluidic access to both sides. We used these nanopores with AFM and total internal reflection fluorescence microscopy (TIRFM) for high resolution imaging and molecular transport measurement. Significantly, membranes over the nanopore were stable for repeated AFM imaging. We studied structure-activity relationship of gap junction hemichannels reconstituted in lipid bilayers. Individual hemichannels in the membrane overlying the nanopore were resolved and transport of hemichannel-permeant LY dye was visualized when the hemichannel was opened by lowering calcium in the medium. This integrated technique will allow direct structure-permeability relationship of many ion channels and receptors.
- Arce, F. T., Meckes, B., Camp, S. M., Garcia, J., Dudek, S. M., & Lal, R. (2013). Heterogeneous elastic response of human lung microvascular endothelial cells to barrier modulating stimuli. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE, 9(7), 875-884.
- Jang, H., Arce, F. T., Ramachandran, S., Kagan, B. L., Lal, R., & Nussinov, R. (2013). Familial Alzheimer's Disease Osaka Mutant (Delta E22) beta-Barrels Suggest an Explanation for the Different A beta(1-40/42) Preferred Conformational States Observed by Experiment. JOURNAL OF PHYSICAL CHEMISTRY B, 117(39), 11518-11529.
- Jang, H., Arce, F. T., Ramachandran, S., Kagan, B. L., Lal, R., & Nussinov, R. (2013). Familial Alzheimer's disease Osaka mutant (ΔE22) β-barrels suggest an explanation for the different Aβ1-40/42 preferred conformational states observed by experiment. The journal of physical chemistry. B, 117(39), 11518-29.More infoAn unusual ΔE693 mutation in the amyloid precursor protein (APP) producing a β-amyloid (Aβ) peptide lacking glutamic acid at position 22 (Glu22) was recently discovered, and dabbed the Osaka mutant (ΔE22). Previously, several point mutations in the Aβ peptide involving Glu22 substitutions were identified and implicated in the early onset of familial Alzheimer's disease (FAD). Despite the absence of Glu22, the Osaka mutant is also associated with FAD, showing a recessive inheritance in families affected by the disease. To see whether this aggregation-prone Aβ mutant could directly relate to the Aβ ion channel-mediated mechanism as observed for the wild type (WT) Aβ peptide in AD pathology, we modeled Osaka mutant β-barrels in a lipid bilayer. Using molecular dynamics (MD) simulations, two conformer ΔE22 barrels with the U-shaped monomer conformation derived from NMR-based WT Aβ fibrils were simulated in explicit lipid environment. Here, we show that the ΔE22 barrels obtain the lipid-relaxed β-sheet channel topology, indistinguishable from the WT Aβ1-42 barrels, as do the outer and pore dimensions of octadecameric (18-mer) ΔE22 barrels. Although the ΔE22 barrels lose the cationic binding site in the pore which is normally provided by the negatively charged Glu22 side chains, the mutant pores gain a new cationic binding site by Glu11 at the lower bilayer leaflet, and exhibit ion fluctuations similar to the WT barrels. Of particular interest, this deletion mutant suggests that toxic WT Aβ1-42 would preferentially adopt a less C-terminal turn similar to that observed for Aβ17-42, and explains why the solid state NMR data for Aβ1-40 point to a more C-terminal turn conformation. The observed ΔE22 barrels conformational preferences also suggest an explanation for the lower neurotoxicity in rat primary neurons as compared to WT Aβ1-42.
- Jang, H., Connelly, L., Arce, F. T., Ramachandran, S., Kagan, B. L., Lal, R., & Nussinov, R. (2013). Mechanisms for the Insertion of Toxic, Fibril-like beta-Amyloid Oligomers into the Membrane. JOURNAL OF CHEMICAL THEORY AND COMPUTATION, 9(1), 822-833.
- Jang, H., Connelly, L., Arce, F. T., Ramachandran, S., Kagan, B. L., Lal, R., & Nussinov, R. (2013). Modeling Variants of Alzheimer's Ion Channels in the Lipid Bilayer formed by an Aggregation-Intermediate beta-Hairpin and E22 Delta Mutant. BIOPHYSICAL JOURNAL, 104(2), 390A-391A.
- Jang, H., Connelly, L., Arce, F. T., Ramachandran, S., Lal, R., Kagan, B. L., & Nussinov, R. (2013). Alzheimer's disease: which type of amyloid-preventing drug agents to employ?. PHYSICAL CHEMISTRY CHEMICAL PHYSICS, 15(23), 8868-8877.
- Patel, N., Seo, C., Arce, F. T., & Lal, R. (2013). Effect of A beta Insertion in DPPC LB Films. BIOPHYSICAL JOURNAL, 104(2), 592A-592A.
- Patel, N., Seo, C., Jang, H., Meckes, B., Connelly, L., Gillman, A., Ramachandran, S., Kagan, B., Nussinov, R., Lal, R., & Arce, F. T. (2013). Effect of A beta Insertion in DPPC LB Films (vol 104, pg 592a, 2013). BIOPHYSICAL JOURNAL, 104(8), 1834-1834.
- Capone, R., Jang, H., Kotler, S. A., Connelly, L., Arce, F. T., Ramachandran, S., Kagan, B. L., Nussinov, R., & Lal, R. (2012). All-D-Enantiomer of beta-Amyloid Peptide Forms Ion Channels in Lipid Bilayers. JOURNAL OF CHEMICAL THEORY AND COMPUTATION, 8(3), 1143-1152.
- Connelly, L. S., Arce, F. T., Jang, H., Capone, R., Kotler, S., Kagan, B., Nussinov, R., & Lal, R. (2012). Alzheimer's beta-Amyloid All-D-Enantiomers and Native All-L-Enantiomers Exhibit Similar Pore Structures in Lipid Bilayers: Atomic Force Microscopy. BIOPHYSICAL JOURNAL, 102(3), 588A-589A.
- Connelly, L., Jang, H., Arce, F. T., Capone, R., Kotler, S. A., Ramachandran, S., Kagan, B. L., Nussinov, R., & Lal, R. (2012). Atomic Force Microscopy and MD Simulations Reveal Pore-Like Structures of All-D-Enantiomer of Alzheimer's beta-Amyloid Peptide: Relevance to the Ion Channel Mechanism of AD Pathology. JOURNAL OF PHYSICAL CHEMISTRY B, 116(5), 1728-1735.
- Connelly, L., Jang, H., Arce, F. T., Capone, R., Kotler, S. A., Ramachandran, S., Kagan, B. L., Nussinov, R., & Lal, R. (2012). Atomic force microscopy and MD simulations reveal pore-like structures of all-D-enantiomer of Alzheimer's β-amyloid peptide: relevance to the ion channel mechanism of AD pathology. The journal of physical chemistry. B, 116(5), 1728-35.More infoAlzheimer's disease (AD) is a protein misfolding disease characterized by a buildup of β-amyloid (Aβ) peptide as senile plaques, uncontrolled neurodegeneration, and memory loss. AD pathology is linked to the destabilization of cellular ionic homeostasis and involves Aβ peptide-plasma membrane interactions. In principle, there are two possible ways through which disturbance of the ionic homeostasis can take place: directly, where the Aβ peptide either inserts into the membrane and creates ion-conductive pores or destabilizes the membrane organization, or, indirectly, where the Aβ peptide interacts with existing cell membrane receptors. To distinguish between these two possible types of Aβ-membrane interactions, we took advantage of the biochemical tenet that ligand-receptor interactions are stereospecific; L-amino acid peptides, but not their D-counterparts, bind to cell membrane receptors. However, with respect to the ion channel-mediated mechanism, like L-amino acids, D-amino acid peptides will also form ion channel-like structures. Using atomic force microscopy (AFM), we imaged the structures of both D- and L-enantiomers of the full length Aβ(1-42) when reconstituted in lipid bilayers. AFM imaging shows that both L- and D-Aβ isomers form similar channel-like structures. Molecular dynamics (MD) simulations support the AFM imaged 3D structures. Previously, we have shown that D-Aβ(1-42) channels conduct ions similarly to their L- counterparts. Taken together, our results support the direct mechanism of Aβ ion channel-mediated destabilization of ionic homeostasis rather than the indirect mechanism through Aβ interaction with membrane receptors.
- Connelly, L., Jang, H., Arce, F. T., Ramachandran, S., Kagan, B. L., Nussinov, R., & Lal, R. (2012). Effects of Point Substitutions on the Structure of Toxic Alzheimer's beta-Amyloid Channels: Atomic Force Microscopy and Molecular Dynamics Simulations. BIOCHEMISTRY, 51(14), 3031-3038.
- Connelly, L., Jang, H., Arce, F. T., Ramachandran, S., Kagan, B. L., Nussinov, R., & Lal, R. (2012). Effects of point substitutions on the structure of toxic Alzheimer's β-amyloid channels: atomic force microscopy and molecular dynamics simulations. Biochemistry, 51(14), 3031-8.More infoAlzheimer's disease (AD) is a misfolded protein disease characterized by the accumulation of β-amyloid (Aβ) peptide as senile plaques, progressive neurodegeneration, and memory loss. Recent evidence suggests that AD pathology is linked to the destabilization of cellular ionic homeostasis mediated by toxic pores made of Aβ peptides. Understanding the exact nature by which these pores conduct electrical and molecular signals could aid in identifying potential therapeutic targets for the prevention and treatment of AD. Here using atomic force microscopy (AFM) and molecular dynamics (MD) simulations, we compared the imaged pore structures with models to predict channel conformations as a function of amino acid sequence. Site-specific amino acid (AA) substitutions in the wild-type Aβ(1-42) peptide yield information regarding the location and significance of individual AA residues to its characteristic structure-activity relationship. We selected two AAs that our MD simulation predicted to inhibit or permit pore conductance. The substitution of Phe19 with Pro has previously been shown to eliminate conductance in the planar lipid bilayer system. Our MD simulations predict a channel-like shape with a collapsed pore, which is supported by the AFM channel images. We suggest that proline, a known β-sheet breaker, creates a kink in the center of the pore and prevents conductance via blockage. This residue may be a viable target for drug development studies aiming to inhibit Aβ from inducing ionic destabilization toxicity. The substitution of Phe20 with Cys exhibits pore structures indistinguishable from the wild type in AFM images. MD simulations predict site 20 to face the solvated pore. Overall, the mutations support the previously predicted β-sheet-based channel structure.
- Jang, H., Capone, R., Kotler, S. A., Arce, F. T., Connelly, L., Ramachandran, S., Kagan, B. L., Lal, R., & Nussinov, R. (2012). Modeling Alzheimer's Ion Channel Structures in Lipid Bilayers Formed by D- and L-Enantiomers of Beta-Amyloid (1-42) Peptide. BIOPHYSICAL JOURNAL, 102(3), 440A-440A.
- Kagan, B. L., Jang, H., Capone, R., Arce, F. T., Ramachandran, S., Lal, R., & Nussinov, R. (2012). Antimicrobial Properties of Amyloid Peptides. MOLECULAR PHARMACEUTICS, 9(4), 708-717.
- Kagan, B. L., Jang, H., Capone, R., Teran Arce, F., Ramachandran, S., Lal, R., & Nussinov, R. (2012). Antimicrobial properties of amyloid peptides. Molecular pharmaceutics, 9(4), 708-17.More infoMore than two dozen clinical syndromes known as amyloid diseases are characterized by the buildup of extended insoluble fibrillar deposits in tissues. These amorphous Congo red staining deposits known as amyloids exhibit a characteristic green birefringence and cross-β structure. Substantial evidence implicates oligomeric intermediates of amyloids as toxic species in the pathogenesis of these chronic disease states. A growing body of data has suggested that these toxic species form ion channels in cellular membranes causing disruption of calcium homeostasis, membrane depolarization, energy drainage, and in some cases apoptosis. Amyloid peptide channels exhibit a number of common biological properties including the universal U-shape β-strand-turn-β-strand structure, irreversible and spontaneous insertion into membranes, production of large heterogeneous single-channel conductances, relatively poor ion selectivity, inhibition by Congo red, and channel blockade by zinc. Recent evidence has suggested that increased amounts of amyloids not only are toxic to its host target cells but also possess antimicrobial activity. Furthermore, at least one human antimicrobial peptide, protegrin-1, which kills microbes by a channel-forming mechanism, has been shown to possess the ability to form extended amyloid fibrils very similar to those of classic disease-forming amyloids. In this paper, we will review the reported antimicrobial properties of amyloids and the implications of these discoveries for our understanding of amyloid structure and function.
- Meckes, B., Arce, F. T., Gillman, A., Mo, A., & Lal, R. (2012). Conducting Atomic Force Microscopy for Simultaneous Imaging of Structure and Ionic Current Through Nanopores. BIOPHYSICAL JOURNAL, 102(3), 586A-586A.
- Arce, F. T., Jang, H., Ramachandran, S., Landon, P. B., Nussinov, R., & Lal, R. (2011). Polymorphism of amyloid beta peptide in different environments: implications for membrane insertion and pore formation. SOFT MATTER, 7(11), 5267-5273.
- Ayala, R., Zhang, C., Yang, D., Hwang, Y., Aung, A., Shroff, S. S., Arce, F. T., Lal, R., Arya, G., & Varghese, S. (2011). Engineering the cell-material interface for controlling stem cell adhesion, migration, and differentiation. BIOMATERIALS, 32(15), 3700-3711.
- Jang, H., Arce, F. T., Mustata, M., Ramachandran, S., Capone, R., Nussinov, R., & Lal, R. (2011). Antimicrobial Protegrin-1 Forms Amyloid-Like Fibrils with Rapid Kinetics Suggesting a Functional Link. BIOPHYSICAL JOURNAL, 100(7), 1775-1783.
- Jang, H., Arce, F. T., Mustata, M., Ramachandran, S., Capone, R., Nussinov, R., & Lal, R. (2011). Antimicrobial protegrin-1 forms amyloid-like fibrils with rapid kinetics suggesting a functional link. Biophysical journal, 100(7), 1775-83.More infoProtegrin-1 (PG-1) is an 18 residues long, cysteine-rich β-sheet antimicrobial peptide (AMP). PG-1 induces strong cytotoxic activities on cell membrane and acts as a potent antibiotic agent. Earlier we reported that its cytotoxicity is mediated by its channel-forming ability. In this study, we have examined the amyloidogenic fibril formation properties of PG-1 in comparison with a well-defined amyloid, the amyloid-β (Aβ(1-42)) peptide. We have used atomic force microscopy (AFM) and thioflavin-T staining to investigate the kinetics of PG-1 fibrils growth and molecular dynamics simulations to elucidate the underlying mechanism. AFM images of PG-1 on a highly hydrophilic surface (mica) show fibrils with morphological similarities to Aβ(1-42) fibrils. Real-time AFM imaging of fibril growth suggests that PG-1 fibril growth follows a relatively fast kinetics compared to the Aβ(1-42) fibrils. The AFM results are in close agreement with results from thioflavin-T staining data. Furthermore, the results indicate that PG-1 forms fibrils in solution. Significantly, in contrast, we do not detect fibrillar structures of PG-1 on an anionic lipid bilayer 2-dioleoyl-sn-glycero-3-phospho-L-serine/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine; only small PG-1 oligomers can be observed. Molecular dynamics simulations are able to identify the presence of these small oligomers on the membrane bilayer. Thus, our current results show that cytotoxic AMP PG-1 is amyloidogenic and capable of forming fibrils. Overall, comparing β-rich AMPs and amyloids such as Aβ, in addition to cytotoxicity and amyloidogenicity, they share a common structural motif, and are channel forming. These combined properties support a functional relationship between amyloidogenic peptides and β-sheet-rich cytolytic AMPs, suggesting that amyloids channels may have an antimicrobial function.
- Jang, H., Arce, F. T., Ramachandran, S., Capone, R., Lal, R., & Nussinov, R. (2011). Modeling Transmembrane beta-Amyloid (A beta) Barrels of Alzheimer's Ion Channels. FASEB JOURNAL, 25.
- Jang, H., Arce, F. T., Ramachandran, S., Capone, R., Lal, R., & Nussinov, R. (2011). Transmembrane beta-Barrel Topology Model for Alzheimer's beta-Amyloid (A beta) Ion Channels. BIOPHYSICAL JOURNAL, 100(3), 201-201.
- Lal, R., Arce, F. T., Ramachandran, S., Connelly, L., & Capone, R. (2011). Nanobiotechnology for neurodegenerative and protein-misfolding diseases. CURRENT OPINION IN BIOTECHNOLOGY, 22, S19-S20.
- Nussinov, R., Jang, H., Arce, F. T., Ramachandran, S., Capone, R., & Lal, R. (2011). Misfolded polymorphic amyloid ion channels present mobile beta-sheet subunits in contrast to conventional ion channels. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 241.
- Ramachandran, S., Arce, F. T., & Lal, R. (2011). Potential role of atomic force microscopy in systems biology. WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE, 3(6), 702-716.
- Capone, R., Mustata, M., Jang, H., Arce, F. T., Nussinov, R., & Lal, R. (2010). Antimicrobial Protegrin-1 Forms Ion Channels: Molecular Dynamic Simulation, Atomic Force Microscopy, and Electrical Conductance Studies. BIOPHYSICAL JOURNAL, 98(11), 2644-2652.
- Dudek, S. M., Chiang, E. T., Camp, S. M., Guo, Y., Zhao, J., Brown, M. E., Singleton, P. A., Wang, L., Desai, A., Arce, F. T., Lal, R., Van, E., Imam, S. Z., & Garcia, J. (2010). Abl Tyrosine Kinase Phosphorylates Nonmuscle Myosin Light Chain Kinase to Regulate Endothelial Barrier Function. MOLECULAR BIOLOGY OF THE CELL, 21(22), 4042-4056.
- Jang, H., Arce, F. T., Capone, R., Ramachandran, S., Lal, R., & Nussinov, R. (2010). Modeling Ion-Permeable beta-Amyloid (A beta) Barrels in the Lipid Bilayer. BIOPHYSICAL JOURNAL, 98(3), 459A-459A.
- Jang, H., Arce, F. T., Ramachandran, S., Capone, R., Azimova, R., Kagan, B. L., Nussinov, R., & Lal, R. (2010). Truncated beta-amyloid peptide channels provide an alternative mechanism for Alzheimer's Disease and Down syndrome. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 107(14), 6538-6543.
- Jang, H., Arce, F. T., Ramachandran, S., Capone, R., Lal, R., & Nussinov, R. (2010). Structural Convergence Among Diverse, Toxic beta-Sheet Ion Channels. JOURNAL OF PHYSICAL CHEMISTRY B, 114(29), 9445-9451.
- Jang, H., Arce, F. T., Ramachandran, S., Capone, R., Lal, R., & Nussinov, R. (2010). beta-Barrel Topology of Alzheimer's beta-Amyloid Ion Channels. JOURNAL OF MOLECULAR BIOLOGY, 404(5), 917-934.
- Arce, F. T., Carlson, R., Monds, J., Veeh, R., Hu, F. Z., Stewart, P. S., Lal, R., Ehrlich, G. D., & Avci, R. (2009). Nanoscale Structural and Mechanical Properties of Nontypeable Haemophilus influenzae Biofilms. JOURNAL OF BACTERIOLOGY, 191(8), 2512-2520.
- Birukova, A. A., Arce, F. T., Moldobaeva, N., Dudek, S. M., Garcia, J., Lal, R., & Birukov, K. G. (2009). Endothelial permeability is controlled by spatially defined cytoskeletal mechanics: Atomic force microscopy force mapping of pulmonary endothelial monolayer. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE, 5(1), 30-41.
- Jang, H., Arce, F. T., Capone, R., Ramachandran, S., Lal, R., & Nussinov, R. (2009). Misfolded Amyloid Ion Channels Present Mobile beta-Sheet Subunits in Contrast to Conventional Ion Channels. BIOPHYSICAL JOURNAL, 97(11), 3029-3037.
- Mustata, M., Capone, R., Jang, H., Arce, F. T., Ramachandran, S., Lal, R., & Nussinov, R. (2009). K3 Fragment of Amyloidogenic beta(2)-Microglobulin Forms Ion Channels: Implication for Dialysis Related Amyloidosis. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 131(41), 14938-14945.
- Arce, F. T., Whitlock, J. L., Birukova, A. A., Birukov, K. G., Arnsdorf, M. F., Lal, R., Garcia, J., & Dudek, S. M. (2008). Regulation of the micromechanical properties of pulmonary endothelium by S1P and thrombin: Role of cortactin. BIOPHYSICAL JOURNAL, 95(2), 886-894.
- Schweitzer, M. H., Suo, Z., Avci, R., Asara, J. M., Allen, M. A., Arce, F. T., & Horner, J. R. (2007). Analyses of soft tissue from Tyrannosaurus rex suggest the presence of protein. SCIENCE, 316(5822), 277-280.
- Arce, F. T., Avci, R., Beech, I. B., Cooksey, K. E., & Wigglesworth-Cooksey, B. (2006). Modification of surface properties of a poly(dimethylsiloxane)-based elastomer, RTV11, upon exposure to seawater. LANGMUIR, 22(17), 7217-7225.
- Liu, F., Arce, F. T., Ramachandran, S., & Lal, R. (2006). Nanomechanics of hemichannel conformations - Connexin flexibility underlying channel opening and closing. JOURNAL OF BIOLOGICAL CHEMISTRY, 281(32), 23207-23217.
- Suci, P. A., Klem, M. T., Arce, F. T., Douglas, T., & Young, M. (2006). Assembly of multilayer films incorporating a viral protein cage architecture. LANGMUIR, 22(21), 8891-8896.
- Suo, Z. Y., Arce, F. T., Avci, R., Thieltges, K., & Spangler, B. (2006). Dendritic structures of poly(ethylene glycol) on silicon nitride and gold surfaces. LANGMUIR, 22(8), 3844-3850.
- Avci, R., Schweitzer, M. H., Boyd, R. D., Wittmeyer, J. L., Arce, F. T., & Calvo, J. O. (2005). Preservation of bone collagen from the late cretaceous period studied by immunological techniques and atomic force microscopy. LANGMUIR, 21(8), 3584-3590.
- Suo, Z., Arce, F. T., Avci, R., Spangler, B., Schweitzer, M. H., Thieltges, K., Wittmeyer, J., & Boyd, R. (2005). Fishing at the nanoscale. GEOCHIMICA ET COSMOCHIMICA ACTA, 69(10), A34-A34.
- Arce, F. T., Avci, R., Beech, I. B., Cooksey, K. E., & Wigglesworth-Cooksey, B. (2004). A live bioprobe for studying diatom-surface interactions. BIOPHYSICAL JOURNAL, 87(6), 4284-4297.
- Avci, R., Schweitzer, M., Boyd, R. D., Wittmeyer, J., Steele, A., Toporski, J., Beech, W., Arce, F. T., Spangler, B., Cole, K. M., & McKay, D. S. (2004). Comparison of antibody-antigen interactions on collagen measured by conventional immunological techniques and atomic force microscopy. LANGMUIR, 20(25), 11053-11063.
- Boyd, R. D., Avci, R., Schweitzer, M., Wittmeyer, J., Arce, F. T., & Calvo, J. (2004). Measuring collagen properties in biomineralized vertebrate tissues by liouid atomic force microscopy.. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 227, U476-U476.
- Arce, F. T., Avci, R., Beech, I. B., Cooksey, K. E., & Wigglesworth-Cooksey, B. (2003). Microelastic properties of minimally adhesive surfaces: A comparative study of RTV11 (TM) and Intersleek elastomers (TM). JOURNAL OF CHEMICAL PHYSICS, 119(3), 1671-1682.
- Arce, F. T., Vela, M. E., Salvarezza, R. C., & Arvia, A. J. (1998). Complex structural dynamics at adsorbed alkanethiol layers at Au(111) single-crystal domains. LANGMUIR, 14(25), 7203-7212.
- Arce, F. T., Vela, M. E., Salvarezza, R. C., & Arvia, A. J. (1998). Dynamic characteristics of adsorbed monolayers of 1-dodecanethiol on gold (111) terraces from in-situ scanning tunneling microscopy imaging. ELECTROCHIMICA ACTA, 44(6-7), 1053-1067.
- Arce, F. T., Vela, M. E., Salvarezza, R. C., & Arvia, A. J. (1998). The dynamic behavior of butanethiol and dodecanethiol adsorbates on Au(111) terraces. JOURNAL OF CHEMICAL PHYSICS, 109(14), 5703-5706.
- Arce, F. T., Vela, M. E., Salvarezza, R. C., & Arvia, A. J. (1997). Comparative study of thiol films on C(0001) and Au(111) surfaces by scanning probe microscopy. SURFACE REVIEW AND LETTERS, 4(4), 637-649.
- GUCKENBERGER, R., ARCE, F. T., HILLEBRAND, A., & HARTMANN, T. (1994). IMAGING OF UNCOATED TOBACCO MOSAIC-VIRUS BY SCANNING-TUNNELING-MICROSCOPY. JOURNAL OF VACUUM SCIENCE & TECHNOLOGY B, 12(3), 1508-1511.