Accelerating the Generalized Born with Molecular Volume and Solvent Accessible Surface Area Implicit Solvent Model Using Graphics Processing Units

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154497/1/jcc26133.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154497/2/jcc26133_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154497/3/jcc26133-sup-0001-supinfo.pd

Effet hydrodynamique sur l’agrégation des peptides β-amyloïde

Un fait marquant et essentiel de la maladie neurodégénérative d’Alzheimer est la formation de plaques amyloïdes dans le cerveau, résultat de l’agrégation des protéines amyloïde-β (Aβ1-40/1-42). Le développement de nouveaux médicaments requiert la compréhension des mécanismes de formation des fibres amyloïdes et la connaissance de la structure et dynamique des oligomères métastables qui sont les vecteurs principaux de la neurotoxicité. Parce que les simulations atomistiques en solvant explicite ne peuvent pas être réalisées sur de grands systèmes pour des temps très longs, nous avons opté pour un modèle protéique gros grain (CG) avec un solvant implicite. Nous nous sommes intéressés dans ces travaux de thèse à clarifier le rôle d’interactions hydrodynamiques(HI) dans la dynamique de formation des agrégats du peptide Aβ(16-22), connu pour former également des fibres amyloïdes. Ces interactions sont essentielles pour modéliser,dans un solvant implicite, les processus se produisant dans des environnements cellulaires très encombrés. Notre approche est basée sur une méthode multi-échelle et multi-physique qui couple les techniques Lattice Boltzmann et de dynamique moléculaire(LBMD). Dans notre système, les interactions médiées par le solvant aqueux sont incluses naturellement. Pour le système moléculaire, nous avons choisi le modèle gros grain à haute résolution OPEP (Optimized Potential for Efficient Protein structure prediction). Pour la première fois, nous avons effectué des simulations quasi tout-atome pour de très grands systèmes contenant des milliers de peptides Aβ ( 16-22). Après avoir correctement réglé le paramètre clé de notre couplage afin d’obtenir la diffusivité expérimentale des monomères et des oligomères du peptide Aβ ( 16-22), nous avons démontré que les HI accélèrent le processus d’agrégation pour des systèmes de taille moyenne (100 Aβ (16-22) peptides) et grande (1000 Aβ (16-22) peptides). Une caractérisation détaillée de la taille des clusters et de l’organisation structurelle des peptides est présentée. Enfin,nous avons examiné comment la concentration affecte la première phase d’agrégation des peptides et leurs structures.The self-assembly of misfolded amyloid-β (Aβ 1-40/1-42) proteins into insoluble fibrils is strongly linked to the pathogenesis of Alzheimer’s disease (AD). The development of new drugs requires the understanding of the mechanisms leading to fibril formation, and the knowledge of the dynamics and structures of the early metastable oligomers which are the main neurotoxic species. Because atomistic simulations in explicit solvent cannot be performed on very large systems for a significant time scale, we resort to a coarse grained (CG) protein model with an implicit solvent. Our investigation enlightens the role of hydrodynamic interactions (HI) in the kinetics of β-amyloidogenesis, interactions which are essential, when an implicit solvent is used, to model processes occurring in highly crowded like-cell environments, among others.Our approach is based on a multi-scale and multi-physics method that couples Lattice Boltzmann and Molecular Dynamics (LBMD) techniques. In our scheme the solvent- mediated interactions are included naturally. As a first step, we focus on Aβ (16-22) peptide, known to form amyloid fibril alone, and we adopt the high resolution CG OPEP (Optimized Potential for Efficient Protein structure prediction) model, developed in our laboratory. For the first time, we have performed quasi-all-atom simulations for very large systems containing thousands of Aβ (16-22) peptides. After the correct tuning of the key parameters of our coupling in order to obtain the experimental diffusivity of Aβ (16-22) monomer and small oligomers, we have demonstrated that HI speed up the aggregation process of medium (100 peptides) and large (1000 peptides) systems. A detailed characterization of the fluctuating clusters along the trajectories is presented in terms of their sizes and the structural organization of the peptides. Finally, we have investigated how changes in the concentration affect the early aggregation phase of the peptides and their structures

Structural, energetic, and electronic properties of La(III)-dimethyl sulfoxide clusters

By using accurate density functional theory calculations, we have studied the cluster complexes of a La(3+) ion interacting with a small number of dimethyl sulfoxide (DMSO) molecules of growing size (from 1 to 12). Extended structural, energetic, and electronic structure analyses have been performed to provide a complete picture of the physical properties that are the basis of the interaction of La(III) with DMSO. Recent experimental data in the solid and liquid phase have suggested a coordination number of 8 DMSO molecules with a square antiprism geometry arranged similarly in the liquid and crystalline phases. By using a cluster approach on the La(3+)(DMSO)n gas phase isolated structures, we have found that the 8-fold geometry, albeit less regular than in the crystal, is probably the most stable cluster. Furthermore, we provide new evidence of a 9-fold complexation geometric arrangement that is competitive (at least energetically) with the 8-fold one and that might suggest the existence of transient structures with higher coordination numbers in the liquid phase

Hydrodynamic effects on beta-amyloid (16-22) peptide aggregation

International audienceComputer simulations based on simplified representations are routinely used to explore the early steps of amyloid aggregation. However, when protein models with implicit solvent are employed, these simulations miss the effect of solvent induced correlations on the aggregation kinetics and lifetimes of metastable states. In this work, we apply the multi-scale Lattice Boltzmann Molecular Dynamics technique (LBMD) to investigate the initial aggregation phases of the amyloid A beta(16-22) peptide. LBMD includes naturally hydrodynamic interactions (HIs) via a kinetic on-lattice representation of the fluid kinetics. The peptides are represented by the flexible OPEP coarse-grained force field. First, we have tuned the essential parameters that control the coupling between the molecular and fluid evolutions in order to reproduce the experimental diffusivity of elementary species. The method is then deployed to investigate the effect of HIs on the aggregation of 100 and 1000 A beta(16-22) peptides. We show that HIs clearly impact the aggregation process and the fluctuations of the oligomer sizes by favouring the fusion and exchange dynamics of oligomers between aggregates. HIs also guide the growth of the leading largest cluster. For the 100 A beta(16-22) peptide system, the simulation of similar to 300 ns allowed us to observe the transition from ellipsoidal assemblies to an elongated and slightly twisted aggregate involving almost the totality of the peptides. For the 1000 A beta(16-22) peptides, a system of unprecedented size at quasi-atomistic resolution, we were able to explore a branched disordered fibril-like structure that has never been described by other computer simulations, but has been observed experimentally. Published by AIP Publishing

Do specific ion effects influence the physical chemistry of aqueous graphene-based supercapacitors? Perspectives from multiscale QMMD simulations

Whether or not specific ion effects determine the charge storage properties of aqueous graphene and graphite-based supercapacitors remains a highly debated topic. In this work we present a multiscale quantum mechanics – classical molecular dynamics (QMMD) investigation of aqueous mono- and divalent salt electrolytes in contact with fully polarizable charged graphene sheets. By computing both the electrochemical double layer (EDL) and quantum capacitance we observe a constant electrode specific capacitance with cationic radii and charge. Counterintuitively, we determine that a switch in the cation adsorption mechanism from inner to outer Helmholtz layers leads to negligible changes to the EDL capacitance, this appears to be due to the robust electronic structure of the graphene electrodes. However, the ability of ions (such as K+) with a relatively low hydration free energy to penetrate the inner Helmholtz plane and adsorb directly on the electrode surface is found to slow their diffusion parallel to the interface. Ions in the outer Helmholtz layer are found to have higher diffusivity at the surface due to their position in ion channels between water layers. Our results show that surface effects such as the surface polarization and the partial dehydration and local structuring of ions on the surface underpin the behaviour of cations at the interface and add a vital new perspective on trends in ion mobilities seen under confinement

Multiscale Aggregation of the Amyloid Aβ 16–22 Peptide: From Disordered Coagulation and Lateral Branching to Amorphous Prefibrils

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Structural, Energetic, and Electronic Properties of La(III)–Dimethyl Sulfoxide Clusters

By using accurate density functional theory calculations, we have studied the cluster complexes of a La³⁺ ion interacting with a small number of dimethyl sulfoxide (DMSO) molecules of growing size (from 1 to 12). Extended structural, energetic, and electronic structure analyses have been performed to provide a complete picture of the physical properties that are the basis of the interaction of La­(III) with DMSO. Recent experimental data in the solid and liquid phase have suggested a coordination number of 8 DMSO molecules with a square antiprism geometry arranged similarly in the liquid and crystalline phases. By using a cluster approach on the La³⁺(DMSO)_<i>n</i> gas phase isolated structures, we have found that the 8-fold geometry, albeit less regular than in the crystal, is probably the most stable cluster. Furthermore, we provide new evidence of a 9-fold complexation geometric arrangement that is competitive (at least energetically) with the 8-fold one and that might suggest the existence of transient structures with higher coordination numbers in the liquid phase

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural and dynamic characterization of all species along the pathways from monomers to fibrils is challenging by experimental and computational means because they involve intrinsically disordered proteins in most diseases. Yet understanding how amyloid species become toxic is the challenge in developing a treatment for these diseases. Here we review what computer, in vitro, in vivo, and pharmacological experiments tell us about the accumulation and deposition of the oligomers of the (Aβ, tau), α-synuclein, IAPP, and superoxide dismutase 1 proteins, which have been the mainstream concept underlying Alzheimer’s disease (AD), Parkinson’s disease (PD), type II diabetes (T2D), and amyotrophic lateral sclerosis (ALS) research, respectively, for many years