1,720,990 research outputs found
Molekulare Nanomaschinen unter der Lupe: Proteindynamik-Simulationen
No full textModerne computergestützte Simulationsverfahren erlauben tiefe Einblicke in biologische Funktionsprozesse. Sie zeigen in atomarer Auflösung, wie Proteine als biologische Nanomaschinen funktionieren. Entscheidend ist dabei deren dynamisches Verhalten. Die Strukturaufklärung liefert meist nur statische Bilder der “eingefrorenen” räumlichen Gestalt der Proteine. Molekulardynamik‐Simulationen machen dagegen Bewegungen sichtbar. Sie konnten zum Beispiel offen legen, wie das Protein F‐ATP‐Synthase das Adenosintriphosphat (ATP) synthetisiert, den zentralen Energieträger des Körpers. Die F‐ATP‐Synthase arbeitet dabei wie ein mechano‐chemischer Dreizylindermotor. Sie ist die kleinste bekannte Nanomaschine der Welt. Ein anderes Beispiel ist die Simulation des komplexen Mechanismus, mit dem das Protein Aquaporin Wassermoleküle durch Zellmembranen schleust
The dynamics and energetics of water permeation and proton exclusion in aquaporins
No full textAquaporins and aquaglyceroporins are passive membrane channels that, in many species, facilitate highly efficient yet strictly selective permeation of water and small solutes across lipid bilayers. Their ability to block proton flux is particularly remarkable, because other aqueous pores and water efficiently conduct protons, via the so-called Grotthuss mechanism. How efficient water permeation is achieved and how it is reconciled with the seemingly contradictory task of strict proton exclusion have been long-standing puzzles. Because neither the dynamics of the water molecules nor the mobility of protons inside the aquaporin channel could be experimentally accessed so far, several groups addressed this challenge using a variety of atomistic computer simulation methods
Partial least squares for dependent data.
Get PDFWe consider the partial least squares algorithm for dependent data and study the consequences of ignoring the dependence both theoretically and numerically. Ignoring nonstationary dependence structures can lead to inconsistent estimation, but a simple modification yields consistent estimation. A protein dynamics example illustrates the superior predictive power of the proposed method
Binding Affinities Controlled by Shifting Conformational Equilibria: Opportunities and Limitations
Get PDFAbstractConformational selection is an established mechanism in molecular recognition. Despite its power to explain binding events, it is hardly used in protein/ligand design to modulate molecular recognition. Here, we explore the opportunities and limitations of design by conformational selection. Using appropriate thermodynamic cycles, our approach predicts the effects of a conformational shift on binding affinity and also allows one to disentangle the effects induced by a conformational shift from other effects influencing the binding affinity. The method is assessed and applied to explain the contribution of a conformational shift on the binding affinity of six ubiquitin mutants showing different conformational shifts in six different complexes
Dynamics and Energetics of Permeation Through Aquaporins. What Do We Learn from Molecular Dynamics Simulations?
No full textAquaporins (AQPs) are a family of integral membrane proteins, which facilitate the rapid and yet highly selective flux of water and other small solutes across biological membranes. Molecular dynamics (MD) simulations contributed substantially to the understanding of the molecular mechanisms that underlie this remarkable efficiency and selectivity of aquaporin channels. This chapter reviews the current state of MD simulations of aquaporins and related aquaglyceroporins as well as the insights these simulations have provided. The mechanism of water permeation through AQPs and methods to determine channel permeabilities from simulations are described. Protons are strictly excluded from AQPs by a large electrostatic barrier and not by an interruption of the Grotthuss mechanism inside the pore. Both the protein's electric field and desolvation effects contribute to this barrier. Permeation of apolar gas molecules such as CO2 through AQPs is accompanied by a large energetic barrier and thus can only be expected in membranes with a low intrinsic gas permeability. Additionally, the insights from simulations into the mechanism of glycerol permeation through the glycerol facilitator GlpF from E. coli are summarized. Finally, MD simulations are discussed that revealed that the aro-matic/arginine constriction region is generally the filter for uncharged solutes, and that AQP selectivity is controlled by a hydrophobic effect and steric restraints
Partial Least-Squares Functional Mode Analysis: Application to the Membrane Proteins AQP1, Aqy1, and CLC-ec1
Get PDFAbstractWe introduce an approach based on the recently introduced functional mode analysis to identify collective modes of internal dynamics that maximally correlate to an external order parameter of functional interest. Input structural data can be either experimentally determined structure ensembles or simulated ensembles, such as molecular dynamics trajectories. Partial least-squares regression is shown to yield a robust solution to the multidimensional optimization problem, with a minimal and controllable risk of overfitting, as shown by extensive cross-validation. Several examples illustrate that the partial least-squares-based functional mode analysis successfully reveals the collective dynamics underlying the fluctuations in selected functional order parameters. Applications to T4 lysozyme, the Trp-cage, the aquaporin channels Aqy1 and hAQP1, and the CLC-ec1 chloride antiporter are presented in which the active site geometry, the hydrophobic solvent-accessible surface, channel gating dynamics, water permeability (pf), and a dihedral angle are defined as functional order parameters. The Aqy1 case reveals a gating mechanism that connects the inner channel gating residues with the protein surface, thereby providing an explanation of how the membrane may affect the channel. hAQP1 shows how the pf correlates with structural changes around the aromatic/arginine region of the pore. The CLC-ec1 application shows how local motions of the gating Glu148 couple to a collective motion that affects ion affinity in the pore
Quantifying artifacts in Ewald simulations of inhomogeneous systems with a net charge
Get PDFEwald summation, which has become the
de facto
standard for computing electrostatic interactions in biomolecular
simulations, formally requires that the simulation box is neutral. For non-neutral systems the Ewald algorithm
implicitly introduces a uniform background charge distribution that e ectively neutralizes the simulation box.
Because a uniform distribution of counter charges typically deviates from the spatial distribution of counterions in
real systems, artifacts may arise, in particular in systems with an inhomogeneous dielectric constant. Here we derive
an analytical expression for the e ect of using an implicit background charge instead of explicit counterions, on
the chemical potential of ions in heterogeneous systems, which (i) provides a quantitative criterium for deciding if
the background charge o ers an acceptable trade-o between artifacts arising from sampling problems and artifacts
arising from the homogeneous background charge distribution; and (ii) can be used to correct this artifact in
certain cases. Because the artifact is due to the
di erence
in charge density between the non-neutral system with a
uniform neutralizing background charge and the real neutral system with a physically correct distribution of explicit
counterions, our model quanti es the artifact in terms of this di erence. We show that for inhomogeneous systems,
such as proteins and membranes in water, the artifact manifests itself by an overstabilization of ions inside the lower
dielectric by tens to even hundreds kilojoules per mole. We have tested the accuracy of our model in molecular
dynamics simulations and found that the error in the calculated free energy for moving a test charge from water into a hexadecane/water slab at di erent net charges of the system and di erent simulation box sizes, is correctly
predicted by the model, con rming that the incorrect distribution of counter charges in the simulation box is solely
responsible for the errors in the PMFs.peerReviewe
Kinetics, statistics, and energetics of lipid membrane electroporation studied by molecular dynamics simulations
Get PDFBoeckmann RA, de Groot BL, Kakorin S, Neumann E, Grubmueller H. Kinetics, statistics, and energetics of lipid membrane electroporation studied by molecular dynamics simulations. BIOPHYSICAL JOURNAL. 2008;95(4):1837-1850.Membrane electroporation is the method to directly transfer bioactive substances such as drugs and genes into living cells, as well as preceding electrofusion. Although much information on the microscopic mechanism has been obtained both from experiment and simulation, the existence and nature of possible intermediates is still unclear. To elucidate intermediates of electropore formation by direct comparison with measured prepore formation kinetics, we have carried out 49 atomistic electroporation simulations on a palmitoyl-oleoyl-phosphatidylcholine bilayer for electric field strengths between 0.04 and 0.7 V/nm. A statistical theory is developed to facilitate direct comparison of experimental (macroscopic) prepore formation kinetics with the (single event) preporation times derived from the simulations, which also allows us to extract an effective number of lipids involved in each pore formation event. A linear dependency of the activation energy for prepore formation on the applied field is seen, with quantitative agreement between experiment and simulation. The distribution of preporation times suggests a four-state pore formation model. The model involves a first intermediate characterized by a differential tilt of the polar lipid headgroups on both leaflets, and a second intermediate (prepore), where a polar chain across the bilayer is formed by 3-4 lipid headgroups and several water molecules, thereby providing a microscopic explanation for the polarizable volume derived previously from the measured kinetics. An average pore radius of 0.47 +/- 0.15 nm is seen, in favorable agreement with conductance measurements and electrooptical experiments of lipid vesicles
Is TEA an inhibitor for human Aquaporin-1?
Get PDFExcessive water uptake through aquaporins can be life threatening, and disregulation of water permeability causes many diseases. Therefore, reversible aquaporin inhibitors are highly desired. In this paper, we identified the binding site for tetraethylammonium (TEA) of the membrane water channel aquaporin-1 by a combined molecular docking and molecular dynamics simulation approach. The binding site identified from docking studies was independently confirmed with an unbiased molecular dynamics simulation of an aquaporin tetramer embedded in a lipid membrane, surrounded by a 100-mM tetraethylammonium solution in water. A third independent assessment of the binding site was obtained by umbrella sampling simulations. These simulations, in addition, revealed a binding affinity of more than 17kJ/mol, corresponding to an IC50 value of << 3mM. Finally, we observed in our simulations a 50% reduction of the water flux in the presence of TEA, in agreement with water permeability measurements on aquaporin expressed in oocytes. These results confirm TEA as a putative lead for an aquaporin-1 inhibitor
Best bang for your buck: GPU nodes for GROMACS biomolecular simulations.
Get PDFThe molecular dynamics simulation package GROMACS runs efficiently on a wide variety of hardware from commodity workstations to high performance computing clusters. Hardware features are well-exploited with a combination of single instruction multiple data, multithreading, and message passing interface (MPI)-based single program multiple data/multiple program multiple data parallelism while graphics processing units (GPUs) can be used as accelerators to compute interactions off-loaded from the CPU. Here, we evaluate which hardware produces trajectories with GROMACS 4.6 or 5.0 in the most economical way. We have assembled and benchmarked compute nodes with various CPU/GPU combinations to identify optimal compositions in terms of raw trajectory production rate, performance-to-price ratio, energy efficiency, and several other criteria. Although hardware prices are naturally subject to trends and fluctuations, general tendencies are clearly visible. Adding any type of GPU significantly boosts a node's simulation performance. For inexpensive consumer-class GPUs this improvement equally reflects in the performance-to-price ratio. Although memory issues in consumer-class GPUs could pass unnoticed as these cards do not support error checking and correction memory, unreliable GPUs can be sorted out with memory checking tools. Apart from the obvious determinants for cost-efficiency like hardware expenses and raw performance, the energy consumption of a node is a major cost factor. Over the typical hardware lifetime until replacement of a few years, the costs for electrical power and cooling can become larger than the costs of the hardware itself. Taking that into account, nodes with a well-balanced ratio of CPU and consumer-class GPU resources produce the maximum amount of GROMACS trajectory over their lifetime. © 2015 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc
- …
