@article{MiettinenMonticelliNedumpullyGovindanetal.2014, author = {Miettinen, Markus S. and Monticelli, Luca and Nedumpully-Govindan, Praveen and Knecht, Volker and Ignatova, Zoya}, title = {Stable polyglutamine dimers can contain beta-hairpins with interdigitated side chains but not a-helices, alpha-nanotubes, beta-pseudohelices, or steric zippers}, series = {Biophysical journal}, volume = {106}, journal = {Biophysical journal}, number = {8}, publisher = {Cell Press}, address = {Cambridge}, issn = {0006-3495}, doi = {10.1016/j.bpj.2014.02.027}, pages = {1721 -- 1728}, year = {2014}, abstract = {A common thread connecting nine fatal neurodegenerative protein aggregation diseases is an abnormally expanded polyglutamine tract found in the respective proteins. Although the structure of this tract in the large mature aggregates is increasingly well described, its structure in the small early aggregates remains largely unknown. As experimental evidence suggests that the most toxic species along the aggregation pathway are the small early ones, developing strategies to alleviate disease pathology calls for understanding the structure of polyglutamine peptides in the early stages of aggregation. Here, we present a criterion, grounded in available experimental data, that allows for using kinetic stability of dimers to assess whether a given polyglutamine conformer can be on the aggregation path. We then demonstrate that this criterion can be assessed using present-day molecular dynamics simulations. We find that although the a-helical conformer of polyglutamine is very stable, dimers of a-helices lack the kinetic stability necessary to support further oligomerization. Dimers of steric zipper, beta-nanotube, and beta-pseudohelix conformers are also too short-lived to initiate aggregation. The beta-hairpin-containing conformers, instead, invariably form very stable dimers when their side chains are interdigitated. Combining these findings with the implications of recent solid-state NMR data on mature fibrils, we propose a possible pathway for the initial stages of polyglutamine aggregation, in which beta-hairpin-containing conformers act as templates for fibril formation.}, language = {en} } @inproceedings{MiettinenMonticelliNedumpullyGovindanetal.2015, author = {Miettinen, Markus S. and Monticelli, Luca and Nedumpully-Govindan, Praveen and Knecht, Volker and Ignatova, Zoya}, title = {Initiating polyglutamine aggregation - computational clarification of the structural details}, series = {Biophysical journal}, volume = {108}, booktitle = {Biophysical journal}, number = {2}, publisher = {Cell Press}, address = {Cambridge}, issn = {0006-3495}, pages = {386A -- 386A}, year = {2015}, language = {en} } @article{MiettinenKnechtMonticellietal.2012, author = {Miettinen, Markus S. and Knecht, Volker and Monticelli, Luca and Ignatova, Zoya}, title = {Assessing polyglutamine conformation in the nucleating event by molecular dynamics simulations}, series = {The journal of physical chemistry : B, Condensed matter, materials, surfaces, interfaces \& biophysical chemistry}, volume = {116}, journal = {The journal of physical chemistry : B, Condensed matter, materials, surfaces, interfaces \& biophysical chemistry}, number = {34}, publisher = {American Chemical Society}, address = {Washington}, issn = {1520-6106}, doi = {10.1021/jp305065c}, pages = {10259 -- 10265}, year = {2012}, abstract = {Polyglutamine (polyQ) diseases comprise a group of dominantly inherited pathology caused by an expansion of an unstable polyQ stretch which is presumed to form beta-sheets. Similar to other amyloid pathologies, polyQ amyloidogenesis occurs via a nucleated polymerization mechanism, and proceeds through energetically unfavorable nucleus whose existence and structure are difficult to detect. Here, we use atomistic molecular dynamics simulations in explicit solvent to assess the conformation of the polyQ stretch in the nucleus that initiates polyQ fibrillization. Comparison of the kinetic stability of various structures of polyQ peptide with a Q-length in the pathological range (Q(40)) revealed that steric zipper or nanotube-like structures (beta-nanotube or beta-pseudohelix) are not kinetically stable enough to serve as a template to initiate polyQ fibrillization as opposed to beta-hairpin-based (beta-sheet and beta-sheetstack) or alpha-helical conformations. The selection of different structures of the polyQ stretch in the aggregation-initiating event may provide an alternative explanation for polyQ aggregate polymorphism.}, language = {en} } @article{JavanainenHammarenMonticellietal.2013, author = {Javanainen, Matti and Hammaren, Henrik and Monticelli, Luca and Jeon, Jae-Hyung and Miettinen, Markus S. and Martinez-Seara, Hector and Metzler, Ralf and Vattulainen, Ilpo}, title = {Anomalous and normal diffusion of proteins and lipids in crowded lipid membranes}, series = {Faraday discussions}, volume = {161}, journal = {Faraday discussions}, number = {1}, publisher = {Royal Society of Chemistry}, address = {Cambridge}, issn = {1359-6640}, doi = {10.1039/c2fd20085f}, pages = {397 -- 417}, year = {2013}, abstract = {Lateral diffusion plays a crucial role in numerous processes that take place in cell membranes, yet it is quite poorly understood in native membranes characterized by, e.g., domain formation and large concentration of proteins. In this article, we use atomistic and coarse-grained simulations to consider how packing of membranes and crowding with proteins affect the lateral dynamics of lipids and membrane proteins. We find that both packing and protein crowding have a profound effect on lateral diffusion, slowing it down. Anomalous diffusion is observed to be an inherent property in both protein-free and protein-rich membranes, and the time scales of anomalous diffusion and the exponent associated with anomalous diffusion are found to strongly depend on packing and crowding. Crowding with proteins also has a striking effect on the decay rate of dynamical correlations associated with lateral single-particle motion, as the transition from anomalous to normal diffusion is found to take place at macroscopic time scales: while in protein-poor conditions normal diffusion is typically observed in hundreds of nanoseconds, in protein-rich conditions the onset of normal diffusion is tens of microseconds, and in the most crowded systems as large as milliseconds. The computational challenge which results from these time scales is not easy to deal with, not even in coarse-grained simulations. We also briefly discuss the physical limits of protein motion. Our results suggest that protein concentration is anything but constant in the plane of cell membranes. Instead, it is strongly dependent on proteins' preference for aggregation.}, language = {en} }