Organisers

• Nick Quirke (University College Dublin & Imperial College London, Ireland)
• Nicolae-Viorel Buchete (School of Physics, University College Dublin, Ireland)
• Suzanne P. Jarvis (University College Dublin, UCD Conway Institute, Ireland)
• Anika Mostaert (University College Dublin, UCD Conway Institute, Ireland)

Supports

Science Foundation Ireland

University College Dublin

Atlantic Centre for Atomistic Modelling - ACAM

   ESF-SimBioMa

Description

This workshop will bring together both experimentalists and theorists with the goal to identify and discuss the state-of-the-art, emerging techniques that could be used to characterize and control molecular aggregation processes and the formation of nanoscale biomolecular structures, with a focus on peptide and protein aggregation. Current and future applications of these structures will be explored by the inclusion of representatives from relevant industries.

Scientific Objectives

Understanding the processes and mechanisms that control the aggregation of molecules and lead to the formation of long-range ordered structures such as fibrils[1-6], nanowires [23,28], membranes and surface coating molecular layers, is crucial to a wide range of fields from biology and medicine to technological applications.[24-30] However, most of the nanoscale structures created through molecular aggregation have particular physical properties that make them difficult to investigate experimentally with classical methods and are thus poorly understood. For example, protein aggregates are generally insoluble and do not crystallize, and therefore their atomic-level structural properties are not amenable for liquid-state NMR or X-ray crystallography studies.[2,6,18] Thus novel and highly innovative approaches are required for both their experimental investigation and for their theoretical modelling. In many cases, both experimental and theoretical studies of molecular aggregates rely heavily on a variety of large scale simulation methods to support and validate their underlying models.[1-3] The main aim of this workshop is to bring together both experimentalists and theorists to identify and discuss the state-of-the-art, emerging techniques that could be used to study and control molecular aggregation processes and the formation of nanoscale structures. Current and future applications of these structures will be explored by the inclusion of representatives from relevant industries.

Motivated by the particularly high interest in the field of protein and peptide aggregation, we propose to focus on this specific aspect of aggregation, discussing the three areas of theory, experiment and application.

Theory. Current simulation methods that could complement experimental investigations and advance the study of biomolecular aggregates: status, limitations and progress

Under Theory, we plan to invite computational/theoretical scientists that work on new methods to study and discuss the complex issues involved in understanding the properties of molecular aggregates, with a focus on fibrils and oligomers. Modern studies cover a wide range of representations from all-atom with explicit solvent representation, [1-3,7-9] to coarse-grained models that could help in overcoming one of the principal bottlenecks in molecular simulations of aggregation: uncommonly large systems sizes. Many of these approaches can theoretically address problems related to easily observable effects: such as effects of mutations/substitutions and more importantly could uncover emerging mechanisms and general principles behind molecular aggregation processes.[1]

Experiment. Structural and kinetic properties of biomolecular aggregates: new techniques, outstanding challenges and limitations.

Under Experiment, we are planning to invite experimental scientists from Ireland and abroad that have been actively developing new, state-of-the-art experimental techniques in the fields of solid state NMR, liquid environment AFM, TEM imaging, X-ray fiber diffraction and single molecule fluorescence. A common feature of many of these recent studies is their use either in their own groups or in the framework of collaboration with computational scientists, of a combination of numerical and molecular simulation methods. The goals are often to test, verify and refine the assumptions used to interpret experimental data and to bridge the gaps between the theoretical models that could be developed for each specific system and the observed physical properties. A typical example is the case of amyloid fibrils where numerical simulations are often used to develop all-atom resolution models that are needed to test and refine the lower resolution data (e.g., inter-residue distances and backbone dihedral angles) available from solid state NMR, TEM, or X-ray fiber diffraction.[1-3,20]

Applications. Designing and preventing aggregation processes.

Applications fall into two broad categories, (a) those that involve the design of self-assembling fibril systems for medical or technological applications and, (b) those involving the prevention or termination of fibrilization in either disease states or to limit the function of amyloid fibrils, for example, in bacterial biofilm formation. In the first area of design there have been very promising results already from the use of self-assembling fibrils for spinal chord repair [27] and thus we aim to have at least one clinician attending the workshop. Technological applications are at an earlier stage of development, but proof of principle demonstrations highlight how protein aggregates can be utilized as conducting wires with appropriate attachments at the fibril surface [28]. In the second area of prevention there is a huge body of work for the development of drugs to treat diseases associated with amyloid protein aggregates such as Alzheimer�s and Parkinson�s disease. One area that will be discussed at the workshop is how in vitro aggregation processes differ from those in vivo and what we can learn from the former with regard to applications in the area of prevention. How best to tackle the latter issue both experimentally and theoretically is a significant challenge, which we also hope to address during the course of the workshop.

References

1. Buchete NV and Hummer G, "Structure and dynamics of parallel beta-sheets, hydrophobic core, and loops in Alzheimer's Abeta fibrils," Biophys. J. 92:3032-3039 (2007)
2. Buchete NV, Tycko R and Hummer G, "Molecular dynamics simulations of Alzheimer's beta-amyloid protofilaments," J. Mol. Biol. 353:804-821 (2005)
3. Luca S, Yau WM, Leapman R, and Tycko R. "Peptide conformation and supramolecular organization in amylin fibrils: Constraints from solid-state NMR", Biochemistry, 46:13505-13522 (2007)
4. Wickner RB, Dyda F, Tycko R. "Amyloid of Rnq1p, the basis of the [PIN+] prion, has a parallel in-register beta-sheet structure" PNAS 105:2403-2408 (2008)
5. Mostaert AS, and Jarvis SP."Beneficial characteristics of mechanically functional amyloid fibrils evolutionarily preserved in natural adhesives". Nanotechnology 18:044010 (2007)
6. Mostaert AS, Higgins MJ, Fukuma T, et al. "Nanoscale mechanical characterisation of amyloid fibrils discovered in a natural adhesive" J. Biol. Phys 32:393-401 (2006)
7. Tarus B, Straub JE, and Thirumalai D. "Structures and free-energy landscapes of the wild type and mutants of the Abeta(21-30) peptide are detennined by an interplay between intrapeptide electrostatic and hydrophobic interactions". J. Mol. Biol., 379:815-829 (2008)
8. Nguyen PH, Li MS, Stock G, Straub JE, and Thirumalai D "Monomer adds to preformed structured oligomers of Abeta-peptides by a two-stage dock-lock mechanism", PNAS, 104: 111-116 (2007)
9. Thirumalai D, Klimov DK, Dima RI, "Emerging ideas on the molecular basis of protein and peptide aggregation", COSB 13:146-159 (2003)
10. Vaiana SM, Ghirlando R, Yau WM, Eaton WA, and Hofrichter J. "Sedimentation studies on human amylin fail to detect low-molecular-weight oligomers", Biophys J. 94: L45-L47 (2008)
11. Eaton WA, Henry ER, Hofrichter J, et al. "Evolution of allosteric models for haemoglobin", IUBMB LIFE 59:586-599 (2007)
12. Petkova AT, Leapman RD, Guo Z, Yau WM, Mattso MP, and Tycko R. "Self-propagating molecular-level polymorphism in Alzheimer"s "-Amyloid Fibrils", Science 307: 262-265 (2005)
13. Ryadnov MG, and Woolfson DN "MaP peptides: Programming the self-assembly of peptide-based mesoscopic matrices", JACS 127: 12407-12415 (2005)
14. Papapostolou D, Smith AM, Atkins EDT, Oliver SB, Ryadnov MG, Serpell LC, and Woolfson DN "Engineering nanoscale order into a designed protein fiber", PNAS 104: 10853-10858 (2007)
15. Smith AM, Acquah SFA, Bone N, Kroto HW, Ryadnov MG, Stevens MSP, Walton DRM, and Woolfson DN " Polar assembly in a designed protein fiber", Angew. Chem. Intl. Ed. 44: 325-328 (2005)
16. Jahn T, Parker M, Homans SW, and Radford SE " Amyloid formation under physiological conditions proceeds via a native-like folding intermediate", Nat. Struct. Mol. Biol. 13: 195-201 (2006)
17. Antzutkin ON, Balbach JJ, and Tycko R "Site-specific identification of non-beta-strand conformations in Alzheimer's beta-amyloid fibrils by solid-state NMR", Biophys. J. 84: 3326"3335 (2003)
18. Tycko R "Progress towards a molecular-level structural understanding of amyloid fibrils", Curr. Opin. Struct. Biol. 14: 96-103 (2004)
19. Makin OS, Atkins E, Sikorski P, Johansson J, and Serpell LC "Molecular basis for amyloid fibril formation and stability", PNAS 102: 315-320 (2005)
20. Nelson R, Sawaya MR, Balbirnie M, Madsen AO, Riekel C, Grothe R, and Eisenberg D " Structure of the cross-beta spine of amyloid-like fibrils" Nature 435: 773"778 (2005)
21. Cleary J, Walsh DM, et al. "Oligomers but not monomers of the amyloid " protein transiently disrupt learned behavior", Nat. Neurosci. 8:79-84 (2005)
22. Keten S, and Buehler MJ, "Geometric Confinement Governs the Rupture Strength of H-bond Assemblies at a Critical Length Scale", Nano Lett. 8: 743-748 (2008)
23. Carny O, Shalev D, and Gazit E (2006) "Fabrication of Coaxial Metal Nanowires Using Self-Assembled Peptide Nanotube Scaffold", Nano Lett. 6: 1594-1597 (2006)
24. Reches M, and Gazit E "Controlled Patterning of Aligned Self-Assembled Peptide Nanotubes", Nature Nanotech. 1: 195-200 (2006)
25. Colmbo G, Soto P, and Gazit E "Self Aggregating Systems and Peptides and their Possible Use", Trends Biotechnol. 25: 211-218 (2007)
26. Ackbarow T, Cheng X, Keten S, and Buehler MJ, "Hierarchies, multiple energy barriers and robustness govern the fracture mechanics of alpha-helical and beta-sheet protein domains ", PNAS 104: 16410-16415 (2007)
27. Silva GA, Czeisler C, Niece KL, Beniash E, Harrington DA, Kessler JA and Stupp SI "Selective differentiation of neural progenitor cells by high-epitope density nanofibers", Science 303: 1352-1355 (2004)
28. Scheibel T, Parthasarathy R, Sawicki G, Lin XM, Jaeger H, and Lindquist SL "Conducting nanowires built by controlled self-assembly of amyloid fibers and selective metal deposition", PNAS 100: 4527-4532 (2003)
29. Supple S, and Quirke N "Short range united atom potentials for alkanes: Decane and nonane", Molecular Simulation 29: 77-82 (2003)
30. Quirke N, "Molecular modelling and simulation: Tools for the modern era," Molecular Simulation 26:1 (2001)