| 1. |
- Larsson, Daniel, 1981-
(författare)
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Exploring the Molecular Dynamics of Proteins and Viruses
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Knowledge about structure and dynamics of the important biological macromolecules — proteins, nucleic acids, lipids and sugars — helps to understand their function. Atomic-resolution structures of macromolecules are routinely captured with X-ray crystallography and other techniques. In this thesis, simulations are used to explore the dynamics of the molecules beyond the static structures.Viruses are machines constructed from macromolecules. Crystal structures of them reveal little to no information about their genomes. In simulations of empty capsids, we observed a correlation between the spatial distribution of chloride ions in the solution and the position of RNA in crystals of satellite tobacco necrosis virus (STNV) and satellite tobacco mosaic virus (STMV). In this manner, structural features of the non-symmetric RNA could also be inferred.The capsid of STNV binds calcium ions on the icosahedral symmetry axes. The release of these ions controls the activation of the virus particle upon infection. Our simulations reproduced the swelling of the capsid upon removal of the ions and we quantified the water permeability of the capsid. The structure and dynamics of the expanded capsid suggest that the disassembly is initiated at the 3-fold symmetry axis.Several experimental methods require biomolecular samples to be injected into vacuum, such as mass-spectrometry and diffractive imaging of single particles. It is therefore important to understand how proteins and molecule-complexes respond to being aerosolized. In simulations we mimicked the dehydration process upon going from solution into the gas phase. We find that two important factors for structural stability of proteins are the temperature and the level of residual hydration. The simulations support experimental claims that membrane proteins can be protected by a lipid micelle and that a non-membrane protein could be stabilized in a reverse micelle in the gas phase. A water-layer around virus particles would impede the signal in diffractive experiments, but our calculations estimate that it should be possible to determine the orientation of the particle in individual images, which is a prerequisite for three-dimensional reconstruction.
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| 2. |
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| 3. |
- Seibert, Mark Marvin, 1980-
(författare)
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Protein Folding and DNA Origami
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis, the folding process of the de novo designed polypeptide chignolin was elucidated through atomic-scale Molecular Dynamics (MD) computer simulations. In a series of long timescale and replica exchange MD simulations, chignolin’s folding and unfolding was observed numerous times and the native state was identified from the computed Gibbs free-energy landscape. The rate of the self-assembly process was predicted from the replica exchange data through a novel algorithm and the structural fluctuations of an enzyme, lysozyme, were analyzed. DNA’s structural flexibility was investigated through experimental structure determination methods in the liquid and gas phase. DNA nanostructures could be maintained in a flat geometry when attached to an electrostatically charged, atomically flat surface and imaged in solution with an Atomic Force Microscope. Free in solution under otherwise identical conditions, the origami exhibited substantial compaction, as revealed by small angle X-ray scattering. This condensation was even more extensive in the gas phase. Protein folding is highly reproducible. It can rapidly lead to a stable state, which undergoes moderate fluctuations, at least for small structures. DNA maintains extensive structural flexibility, even when folded into large DNA origami. One may reflect upon the functional roles of proteins and DNA as a consequence of their atomic-level structural flexibility. DNA, biology’s information carrier, is very flexible and malleable, adopting to ever new conformations. Proteins, nature’s machines, faithfully adopt highly reproducible shapes to perform life’s functions robotically.
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| 4. |
- Hosseini, A. Najla, et al.
(författare)
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Simulations of Amyloid-Forming Peptides in the Crystal State
- 2023
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Ingår i: The Protein Journal. - : Springer. - 1572-3887 .- 1875-8355. ; 42:3, s. 192-204
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Tidskriftsartikel (refereegranskat)abstract
- There still is little treatment available for amyloid diseases, despite their significant impact on individuals and the social and economic implications for society. One reason for this is that the physical nature of amyloid formation is not understood sufficiently well. Therefore, fundamental research at the molecular level remains necessary to support the development of therapeutics. A few structures of short peptides from amyloid-forming proteins have been determined. These can in principle be used as scaffolds for designing aggregation inhibitors. Attempts to this end have often used the tools of computational chemistry, in particular molecular simulation. However, few simulation studies of these peptides in the crystal state have been presented so far. Hence, to validate the capability of common force fields (AMBER19SB, CHARMM36m, and OPLS-AA/M) to yield insight into the dynamics and structural stability of amyloid peptide aggregates, we have performed molecular dynamics simulations of twelve different peptide crystals at two different temperatures. From the simulations, we evaluate the hydrogen bonding patterns, the isotropic B-factors, the change in energy, the Ramachandran plots, and the unit cell parameters and compare the results with the crystal structures. Most crystals are stable in the simulations but for all force fields there is at least one that deviates from the experimental crystal, suggesting more work is needed on these models.
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| 5. |
- Malmerberg, Erik, 1980, et al.
(författare)
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Time-Resolved WAXS Reveals Accelerated Conformational Changes in Iodoretinal-Substituted Proteorhodopsin.
- 2011
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Ingår i: Biophysical journal. - : Elsevier BV. - 1542-0086 .- 0006-3495. ; 101:6, s. 1345-53
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Tidskriftsartikel (refereegranskat)abstract
- Time-resolved wide-angle x-ray scattering (TR-WAXS) is an emerging biophysical method which probes protein conformational changes with time. Here we present a comparative TR-WAXS study of native green-absorbing proteorhodopsin (pR) from SAR86 and a halogenated derivative for which the retinal chromophore has been replaced with 13-desmethyl-13-iodoretinal (13-I-pR). Transient absorption spectroscopy differences show that the 13-I-pR photocycle is both accelerated and displays more complex kinetics than native pR. TR-WAXS difference data also reveal that protein structural changes rise and decay an order-of-magnitude more rapidly for 13-I-pR than native pR. Despite these differences, the amplitude andnature of the observed helical motions are not significantly affected by the substitution of the retinal's C-20 methyl group with an iodine atom. Molecular dynamics simulations indicate that a significant increase in free energy is associated with the 13-cis conformation of 13-I-pR, consistent with our observation that the transient 13-I-pR conformational state is reached more rapidly. We conclude that although the conformational trajectory is accelerated, the major transient conformation of pR is unaffected by the substitution of an iodinated retinal chromophore.
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| 6. |
- Manzetti, Sergio, 1975-
(författare)
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Computational Ecotoxicology
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Human society has progressed by polluting ecosystems since at least the early industrial revolution. Large amounts of harmful chemical compounds have been dispersed in soils, seas, ground waters and wildlife habitats by industrial and anthropomorphic activities over the last two centuries, leading to a persistent toxicological load on the environment. Pollution is a threat to biodiversity, to the health of ecosystems, and to all living organisms. Advances in environmental sciences are needed so that pollutants can be distinguished from harmless compounds. New methods could ease the enormous task of sorting out hazardous chemicals, and also facilitate the study of existing problems in ecotoxicology, which are often hampered by insufficient data. In our research, we apply the methods of computational chemistry to predict the interactions of various toxins, carcinogens, nanoparticles and xenobiotics with proteins, DNA, and cell membranes. Methods such as molecular dynamics simulations, docking, and quantum chemistry are at the core of these studies, each having its role in facilitating the enormous task of transforming in vitro ecotoxicology to in silico ecotoxicology. We perform detailed studies of a few compounds and receptors, as well as larger, more comprehensive groups of compounds. We also outline approaches for drawing computational conclusions about the molecular behaviour of various potential environmental toxins by modelling their interactions with DNA and proteins, and we use partition coefficients to describe their ability to permeate the cell membrane. Methods for studying the purification of pollutants from essential sources, such as water, are proposed. We also investigate the emerging problem of nanoparticle pollution and propose computational approaches to model the formation of nanoparticles from combustion emissions and the interactions of such particles with atmospheric components.
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| 7. |
- Hess, Berk, et al.
(författare)
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GROMACS 4.0 : Algorithms for highly efficient, load balanced, and scalable molecular simulation
- 2008
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 4:2, s. 435-
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Tidskriftsartikel (refereegranskat)abstract
- Molecular simulation is an extremely useful, but computationally very expensive tool for studies of chemical and biomolecular systems. Here, we present a new implementation of our molecular simulation toolkit GROMACS which now both achieves extremely high performance on single processors from algorithmic optimizations and hand-coded routines and simultaneously scales very well on parallel machines. The code encompasses a minimal-communication domain decomposition algorithm, full dynamic load balancing, a state-of-the-art parallel constraint solver, and efficient virtual site algorithms that allow removal of hydrogen atom degrees of freedom to enable integration time steps up to 5 fs; for atomistic simulations also in parallel. To improve the scaling properties of the common particle mesh Ewald electrostatics algorithms, we have in addition used a Multiple-Program, Multiple-Data approach, with separate node domains responsible for direct and reciprocal space interactions. Not only does this combination of algorithms enable extremely long simulations of large systems but also it provides that simulation performance on quite modest numbers of standard cluster nodes.
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| 8. |
- Larsson, Daniel, et al.
(författare)
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Screening for the Location of RNA Using the Chloride Ion Distribution in Simulations of Virus Capsids
- 2012
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 8:7, s. 2474-2483
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Tidskriftsartikel (refereegranskat)abstract
- The complete structure of the genomic material inside a virus capsid remains elusive, although a limited amount of symmetric nucleic acid can be resolved in the crystal structure of 17 icosahedral viruses. The negatively charged sugar-phosphate backbone of RNA and DNA as well as the large positive charge of the interior surface of the virus capsids suggest that electrostatic complementarity is an important factor in the packaging of the genomes in these viruses. To test how much packing information is encoded by the electrostatic and steric envelope of the capsid interior, we performed extensive all-atom molecular dynamics (MD) simulations of virus capsids with explicit water molecules and solvent ions. The model systems were two small plant viruses in which significant amounts of RNA has been observed by X-ray crystallography: satellite tobacco mosaic virus (STMV, 62% RNA visible) and satellite tobacco necrosis virus (STNV, 34% RNA visible). Simulations of half-capsids of these viruses with no RNA present revealed that the binding sites of RNA correlated well with regions populated by chloride ions, suggesting that it is possible to screen for the binding sites of nucleic acids by determining the equilibrium distribution of negative ions. By including the crystallographically resolved RNA in addition to ions, we predicted the localization of the unresolved RNA in the viruses. Both viruses showed a hot-spot for RNA binding at the S-fold symmetry axis. The MD simulations were compared to predictions of the chloride density based on nonlinear Poisson-Boltzmann equation (PBE) calculations with mobile ions. Although the predictions are superficially similar, the PBE calculations overestimate the ion concentration close to the capsid surface and underestimate it far away, mainly because protein dynamics is not taken into account. Density maps from chloride screening can be used to aid in building atomic models of packaged virus genomes. Knowledge of the principles of genome packaging might be exploited for both antiviral therapy and technological applications.
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| 9. |
- Larsson, Daniel, et al.
(författare)
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Virus Capsid Dissolution Studied by Microsecond Molecular Dynamics Simulations
- 2012
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Ingår i: PloS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 8:5, s. e1002502-
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Tidskriftsartikel (refereegranskat)abstract
- Dissolution of many plant viruses is thought to start with swelling of the capsid caused by calcium removal following infection, but no high-resolution structures of swollen capsids exist. Here we have used microsecond all-atom molecular simulations to describe the dynamics of the capsid of satellite tobacco necrosis virus with and without the 92 structural calcium ions. The capsid expanded 2.5% upon removal of the calcium, in good agreement with experimental estimates. The water permeability of the native capsid was similar to that of a phospholipid membrane, but the permeability increased 10-fold after removing the calcium, predominantly between the 2-fold and 3-fold related subunits. The two calcium binding sites close to the icosahedral 3-fold symmetry axis were pivotal in the expansion and capsid-opening process, while the binding site on the 5-fold axis changed little structurally. These findings suggest that the dissociation of the capsid is initiated at the 3-fold axis.
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| 10. |
- Ghahremanpour, Mohammad Mehdi
(författare)
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Alexandria: A General Drude Polarizable Force Field with Spherical Charge Density
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Molecular-mechanical (MM) force fields are mathematical functions that map the geometry of a molecule to its associated energy. MM force fields have been extensively used for an atomistic view into the dynamic and thermodynamics of large molecular systems in their condensed phase. Nevertheless, the grand challenge in force field development—which remains to be addressed—is to predict properties of materials with different chemistries and in all their physical phases. Force fields are, in principle, derived through supervised machine learning methods. Therefore, the first step toward more accurate force fields is to provide high-quality reference data from which the force fields can learn. Thus, we benchmarked quantum-mechanical methods—at different levels of theory—in predicting of molecular energetics and electrostatic properties. As the result, the Alexandria library was released as an open access database of molecular properties. The second step is to use potential functions describing interactions between molecules accurately. For this, we incorporated electronic polarization and charge penetration effects into the Alexandria force field. The Drude model was used for the explicit inclusion of electronic polarization. The distribution of the atomic charges was described by either a 1s-Gaussian or an ns-Slater density function to account for charge penetration effects. Moreover, the 12-6 Lennard-Jones (LJ) potential function, commonly used in force fields, was replaced by the Wang-Buckingham (WBK) function to describe the interaction of two particles at very short distances. In contrast to the 12-6 LJ function, the WBK function is well behaved at short distances because it has a finite limit as the distance between two particles approaches zero. The third step is free and open source software (FOSS) for systematic optimization of the built-in force field parameters. For this, we developed the Alexandria chemistry toolkit that is currently part of the GROMACS software package. With these three steps, the Alexandria force field was developed for alkali halides and for organic compounds consisting of (H, C, N, O, S, P) and halogens (F, Cl, Br, I). We demonstrated that the Alexandria force field described alkali halides in gas, liquid, and solid phases with an overall performance better than the benchmarked reference force fields. We also showed that the Alexandria force field predicted the electrostatics of isolated molecules and molecular complexes in agreement with the density functional theory at the B3LYP/aug-cc-pVTZ level of theory.
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