Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik, KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik, Kasson, Peter M., Lindahl, Erik, and Pande, Vijay S.
Journal of the American Chemical Society. 133(11):3812-3815
Natural Sciences, Biological Sciences, Naturvetenskap, Biologiska vetenskaper, Biophysics, Biofysik, Chemical Sciences, Theoretical Chemistry, Kemi, Teoretisk kemi, Bioinformatics and Systems Biology, Bioinformatik och systembiologi, NATURAL SCIENCES, Physics, Condensed matter physics, Biological physics, NATURVETENSKAP, Fysik, Kondenserade materiens fysik, Biologisk fysik, SRA - E-Science (SeRC), and SRA - E-vetenskap (SeRC)
Membrane interfaces are critical to many cellular functions, yet the vast array of molecular components involved make the fundamental physics of interaction difficult to define. Water has been shown to play an important role in the dynamics of small biological systems, for example when trapped in hydrophobic regions, but the molecular details of water have generally been thought dispensable when considering large membrane interfaces. Nevertheless, spectroscopic data indicate that water has distinct, ordered behavior near membrane surfaces. While coarse-grained simulations have achieved success recently in aiding understanding the dynamics of membrane assemblies, it is natural to ask, does the missing chemical nature of water play an important role? We have therefore performed atomic-resolution simulations of vesicle fusion to understand the role of chemical detail, particularly the molecular structure of water, in membrane fusion and at membrane interfaces more generally. These membrane interfaces present a form of hydrophilic confinement, yielding surprising, non-bulk-like water behavior.
There are many unresolved questions regarding the role of water in protein folding. Does water merely induce hydrophobic forces, or does the discrete nature of water play a structural role in folding? Are the nonadditive aspects of water important in determining the folding mechanism? To help to address these questions, we have performed simulations of the folding of a model protein (BBA5) in explicit solvent. Starting 10,000 independent trajectories from a fully unfolded conformation, we have observed numerous folding events, making this work a comprehensive study of the kinetics of protein folding starting from the unfolded state and reaching the folded state and with an explicit solvation model and experimentally validated rates. Indeed, both the raw TIP3P folding rate (4.5 +/- 2.5 micros) and the diffusion-constant corrected rate (7.5 +/- 4.2 micros) are in strong agreement with the experimentally observed rate of 7.5 +/- 3.5 micros. To address the role of water in folding, the mechanism is compared with that predicted from implicit solvation simulations. An examination of solvent density near hydrophobic groups during folding suggests that in the case of BBA5, there are water-induced effects not captured by implicit solvation models, including signs of a "concurrent mechanism" of core collapse and desolvation.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik, Kasson, Peter M, Lindahl, Erik, and Pande, Vijay S
PloS Computational Biology. 6(6)
Natural Sciences, Chemical Sciences, Theoretical Chemistry, Naturvetenskap, Kemi, Teoretisk kemi, Biological Sciences, Biochemistry and Molecular Biology, Biologiska vetenskaper, Biokemi och molekylärbiologi, NATURAL SCIENCES, Chemistry, Biochemistry, NATURVETENSKAP, and Biokemi
Membrane fusion is essential to both cellular vesicle trafficking and infection by enveloped viruses. While the fusion protein assemblies that catalyze fusion are readily identifiable, the specific activities of the proteins involved and nature of the membrane changes they induce remain unknown. Here, we use many atomic-resolution simulations of vesicle fusion to examine the molecular mechanisms for fusion in detail. We employ committor analysis for these million-atom vesicle fusion simulations to identify a transition state for fusion stalk formation. In our simulations, this transition state occurs when the bulk properties of each lipid bilayer remain in a lamellar state but a few hydrophobic tails bulge into the hydrophilic interface layer and make contact to nucleate a stalk. Additional simulations of influenza fusion peptides in lipid bilayers show that the peptides promote similar local protrusion of lipid tails. Comparing these two sets of simulations, we obtain a common set of structural changes between the transition state for stalk formation and the local environment of peptides known to catalyze fusion. Our results thus suggest that the specific molecular properties of individual lipids are highly important to vesicle fusion and yield an explicit structural model that could help explain the mechanism of catalysis by fusion proteins.
Biomolecular simulation is a core application on supercomputers, but it is exceptionally difficult to achieve the strong scaling necessary to reach biologically relevant timescales. Here, we present a new paradigm for parallel adaptive molecular dynamics and a publicly available implementation: Copernicus. This framework combines performance-leading molecular dynamics parallelized on three levels (SIMD, threads, and message-passing) with kinetic clustering, statistical model building and real-time result monitoring. Copernicus enables execution as single parallel jobs with automatic resource allocation. Even for a small protein such as villin (9,864 atoms), Copernicus exhibits near-linear strong scaling from 1 to 5,376 AMD cores. Starting from extended chains we observe structures 0.6 Å from the native state within 30h, and achieve sufficient sampling to predict the native state without a priori knowledge after 80-90h. To match Copernicus'efficiency, a classical simulation would have to exceed 50 microseconds per day, currently infeasible even with custom hardware designed for simulations.