TY - JOUR A1 - Javanainen, Matti A1 - Hammaren, Henrik A1 - Monticelli, Luca A1 - Jeon, Jae-Hyung A1 - Miettinen, Markus S. A1 - Martinez-Seara, Hector A1 - Metzler, Ralf A1 - Vattulainen, Ilpo T1 - Anomalous and normal diffusion of proteins and lipids in crowded lipid membranes JF - Faraday discussions N2 - 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. Y1 - 2013 U6 - https://doi.org/10.1039/c2fd20085f SN - 1359-6640 VL - 161 IS - 1 SP - 397 EP - 417 PB - Royal Society of Chemistry CY - Cambridge ER - TY - JOUR A1 - Miettinen, Markus S. A1 - Knecht, Volker A1 - Monticelli, Luca A1 - Ignatova, Zoya T1 - Assessing polyglutamine conformation in the nucleating event by molecular dynamics simulations JF - The journal of physical chemistry : B, Condensed matter, materials, surfaces, interfaces & biophysical chemistry N2 - 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. Y1 - 2012 U6 - https://doi.org/10.1021/jp305065c SN - 1520-6106 VL - 116 IS - 34 SP - 10259 EP - 10265 PB - American Chemical Society CY - Washington ER - TY - JOUR A1 - Miettinen, Markus S. A1 - Monticelli, Luca A1 - Nedumpully-Govindan, Praveen A1 - Knecht, Volker A1 - Ignatova, Zoya T1 - Stable polyglutamine dimers can contain beta-hairpins with interdigitated side chains but not a-helices, alpha-nanotubes, beta-pseudohelices, or steric zippers JF - Biophysical journal N2 - 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. Y1 - 2014 U6 - https://doi.org/10.1016/j.bpj.2014.02.027 SN - 0006-3495 SN - 1542-0086 VL - 106 IS - 8 SP - 1721 EP - 1728 PB - Cell Press CY - Cambridge ER - TY - CHAP A1 - Miettinen, Markus S. A1 - Monticelli, Luca A1 - Nedumpully-Govindan, Praveen A1 - Knecht, Volker A1 - Ignatova, Zoya T1 - Initiating polyglutamine aggregation - computational clarification of the structural details T2 - Biophysical journal Y1 - 2015 SN - 0006-3495 SN - 1542-0086 VL - 108 IS - 2 SP - 386A EP - 386A PB - Cell Press CY - Cambridge ER -