The analysis of biomolecular computer simulations has become a challenge because the amount of ou... more The analysis of biomolecular computer simulations has become a challenge because the amount of output data is now routinely in the terabyte range. We evaluated if this challenge can be met by a parallel map-reduce approach with the Dask parallel computing library for task-graph based computing coupled with our MDAnalysis Python library for the analysis of molecular dynamics (MD) simulations. We performed a representative performance evaluation , taking into account the highly heterogeneous computing environment that researchers typically work in together with the diversity of existing file formats for MD trajectory data. We found that the underlying storage system (solid state drives, parallel file systems, or simple spinning platter disks) can be a deciding performance factor that leads to data ingestion becoming the primary bottleneck in the analysis work flow. However, the choice of the data file format can mitigate the effect of the storage system; in particular, the commonly us...
Transport of ions and small molecules across the cell membrane against electrochemical gradients ... more Transport of ions and small molecules across the cell membrane against electrochemical gradients is catalyzed by integral membrane proteins that use a source of free energy to drive the energetically uphill flux of the transported substrate. Secondary active transporters couple the spontaneous influx of a "driving" ion such as Na+ or H+ to the flux of the substrate. The thermodynamics of such cyclical non-equilibrium systems are well understood and recent work has focused on the molecular mechanism of secondary active transport. The fact that these transporters change their conformation between an inward-facing and outward-facing conformation in a cyclical fashion, called the alternating access model, is broadly recognized as the molecular framework in which to describe transporter function. However, only with the advent of high resolution crystal structures and detailed computer simulations has it become possible to recognize common molecular-level principles between disp...
Na+/H+ exchangers catalyse an ion-exchange activity that is carried out in most, if not all cells... more Na+/H+ exchangers catalyse an ion-exchange activity that is carried out in most, if not all cells. SLC9B2, also known as NHA2, correlates with the long-sought after sodium/lithium (Na+/Li+) exchanger linked to the pathogenesis of diabetes mellitus and essential hypertension in humans. Despite its functional importance, structural information and the molecular basis of its ion-exchange mechanism have been lacking. Here, we report the cryo EM structures of bison NHA2 in detergent and in nanodiscs at 3.0 and 3.5 Å resolution, respectively. NHA2 shares closest structural similarity to the bacterial electrogenic Na+/H+ antiporter NapA, rather than other mammalian SLC9A members. Nevertheless, SSM-based electrophysiology results with NHA2 show the catalysis of electroneutral rather than electrogenic ion exchange, and the ion-binding site is quite distinctive, with a tryptophan-arginine- glutamate triad separated from the well-established ion-binding aspartates. These triad residues fine-tu...
In the biomolecular simulation (BMS) community, classical molecular dynamics (MD) simulations ena... more In the biomolecular simulation (BMS) community, classical molecular dynamics (MD) simulations enable the elucidation of the relationship between the structure of biomolecules such as proteins, nucleic acids, or lipids and their function via their dynamics. MD simulations account for approximately one quarter of the service units used on XSEDE resources. Although traditionally the generation of the data has been the computational bottleneck and has been highly optimized, more and more the analysis of the data is becoming a rate limiting step. Within the NSF DIBBs SPIDAL project we have been working on leveraging HPC resources for the analysis of BMS data [1], starting from two widely adopted software packages in the community, cpptraj [2] and MDAnalysis [3,4].
Currently, computation of the distance_array and rmsd for each frame in a molecular dynamics traj... more Currently, computation of the distance_array and rmsd for each frame in a molecular dynamics trajectory in MDAnalysis is a computationally intensive process. MDAnalysis (mdanalysis.org) is an open source library that allows for the analysis of molecular dynamics simulations. The goal of this REU was to speed up parts of MDAnalysis. We created a GPU based program through PyCUDA that allows us to compute distance arrays. PyCUDA (https:// mathema.tician.de/software/pycuda/) is a package that allows us to access NVIDIA’s CUDA API via python. Unfortunately, even though that it was evident that GPU’s do compute distance arrays faster than CPU’s, the transfer time between the local memory and the GPU is long enough such CPU computation is still faster. We also made slight modifications to the rmsd calculations to improve speeds by up to 30%.
Molecular dynamics (MD) computer simulations help elucidate details of the molecular processes in... more Molecular dynamics (MD) computer simulations help elucidate details of the molecular processes in complex biological systems, from protein dynamics to drug discovery. One major issue is that these MD simulation files are now commonly terabytes in size, which means analyzing the data from these files becomes a painstakingly expensive task. In the age of national supercomputers, methods of parallel analysis are becoming a necessity for the efficient use of time and high performance computing (HPC) resources but for any approach to parallel analysis, simply reading the file from disk becomes the performance bottleneck that limits overall analysis speed. One promising way around this file I/O hurdle is to use a parallel message passing interface (MPI) implementation with the HDF5 (Hierarchical Data Format 5) file format to access a single file simultaneously with numerous processes on a parallel file system. Our previous feasibility study suggested that this combination can lead to favo...
Na+/H+ exchangers catalyse an ion-exchange activity that is carried out in most, if not all cells... more Na+/H+ exchangers catalyse an ion-exchange activity that is carried out in most, if not all cells. SLC9B2, also known as NHA2, correlates with the long-sought after sodium/lithium (Na+/Li+) exchanger linked to the pathogenesis of diabetes mellitus and essential hypertension in humans. Despite its functional importance, structural information and the molecular basis of its ion-exchange mechanism have been lacking. Here, we report the cryo EM structures of bison NHA2 in detergent and in nanodiscs at 3.0 and 3.5 Å resolution, respectively. NHA2 shares closest structural similarity to the bacterial electrogenic Na+/H+ antiporter NapA, rather than other mammalian SLC9A members. Nevertheless, SSM-based electrophysiology results with NHA2 show the catalysis of electroneutral rather than electrogenic ion exchange, and the ion-binding site is quite distinctive, with a tryptophan-arginine- glutamate triad separated from the well-established ion-binding aspartates. These triad residues fine-tu...
To what extent must a hydrophobic gate expand for the channel to count as open? We address this q... more To what extent must a hydrophobic gate expand for the channel to count as open? We address this question using the nicotinic acetylcholine receptor (nAChR) as the exemplar. The nAChR is an integral membrane protein which forms a cation selective channel gated by neurotransmitter binding to its extracellular domain. A hydrophobic gating model has been proposed for the nAChR, whereby the pore is incompletely occluded in the closed state channel, with a narrow hydrophobic central gate region which presents an energetic barrier to ion permeation. The nAChR pore is lined by a parallel bundle of five M2 alpha-helices, with the gate formed by three rings of hydrophobic sidechains (9', 13', and 17' of M2). A number of models have been proposed to describe the nature of the conformational change underlying the closed to open transition of the nAChR. These models involve different degrees of M2 helix displacement, rotation, and/or kinking. In this study, we use a simple pore expan...
Analysis of molecular dynamics (MD) trajectories is becoming more and more challenging with simul... more Analysis of molecular dynamics (MD) trajectories is becoming more and more challenging with simulation times routinely exceeding microseconds (with millions of frames) and increasing in size (with millions of particles). The MDAnalysis library (http://mdanalysis.org) is a versatile open source package that provides a foundation for analysing trajectories, with a particular emphasis on biomolecular simulations. In order to improve MDAnalysis for large simulations, we developed a set of non-trivial benchmarking systems of variable sizes. We generated a modular library of lipid vesicles with the coarse-grained Dry Martini force field, ranging in size from 10 nm to 30 nm radius. These vesicles can be combined in larger multi-vesicle systems in order to produce a range of benchmark systems with variable particle numbers. The systems will also allow us to address the question under which conditions vesicles fuse. We generated simulation systems with up to six vesicles and 3.5 million part...
We predicted water-octanol partition coefficients for the molecules in the SAMPL7 challenge with ... more We predicted water-octanol partition coefficients for the molecules in the SAMPL7 challenge with explicit solvent classical molecular dynamics (MD) simulations. Water hydration free energies and octanol solvation free energies were calculated with a windowed alchemical free energy approach. Three commonly used force fields (AMBER GAFF, CHARMM CGenFF, OPLS-AA) were tested. Special emphasis was placed on converging all simulations, using a criterion developed for the SAMPL6 challenge. In aggregate, over 1000 μ\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\mu$$\end{document}s of simulations were performed, with some free energy windows remaining not fully converged even after 1 μ\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\mu$$\end{document}s of simulation time. Nevertheless, the amount of sampling produced logPow\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\log P_{ow}$$\end{document} estimates with a precision of 0.1 log units or better for converged simulations. Despite being probably as fully sampled as can expected and is feasible, the agreement with experiment remained modest for all force fields, with no force field performing better than 1.6 in root mean squared error. Overall, our results indicate that a large amount of sampling is necessary to produce precise logPow\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\log P_{ow}$$\end{document} predictions for the SAMPL7 compounds and that high precision does not necessarily lead to high accuracy. Thus, fundamental problems remain to be solved for physics-based logPow\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\log P_{ow}$$\end{document} predictions.
YiiP is a secondary transporter that couples Zn2+ transport to the proton motive force. Structura... more YiiP is a secondary transporter that couples Zn2+ transport to the proton motive force. Structural studies of YiiP from prokaryotes as well as Znt8 from humans revealed three different Zn2+ sites and a conserved homodimeric architecture. These structures define the inward-facing and outward-facing states that characterize the archetypal alternating access mechanism of transport. To study effects of Zn2+ binding on the conformational transition, we have used a YiiP/Fab complex for single-particle cryo-EM together with Molecular Dynamics simulation to compare structures of YiiP from S. oneidensis in presence and absence of Zn2+. Without Zn2+, YiiP exhibits enhanced flexibility and adopts a novel conformation that appears to be an intermediate state. The transition closes a hydrophobic gate and is controlled by the Zn2+ site at the cytoplasmic membrane interface. This work enhances our understanding of individual Zn2+ binding sites and their role in the conformational dynamics that gov...
The analysis of biomolecular computer simulations has become a challenge because the amount of ou... more The analysis of biomolecular computer simulations has become a challenge because the amount of output data is now routinely in the terabyte range. We evaluated if this challenge can be met by a parallel map-reduce approach with the Dask parallel computing library for task-graph based computing coupled with our MDAnalysis Python library for the analysis of molecular dynamics (MD) simulations. We performed a representative performance evaluation , taking into account the highly heterogeneous computing environment that researchers typically work in together with the diversity of existing file formats for MD trajectory data. We found that the underlying storage system (solid state drives, parallel file systems, or simple spinning platter disks) can be a deciding performance factor that leads to data ingestion becoming the primary bottleneck in the analysis work flow. However, the choice of the data file format can mitigate the effect of the storage system; in particular, the commonly us...
Transport of ions and small molecules across the cell membrane against electrochemical gradients ... more Transport of ions and small molecules across the cell membrane against electrochemical gradients is catalyzed by integral membrane proteins that use a source of free energy to drive the energetically uphill flux of the transported substrate. Secondary active transporters couple the spontaneous influx of a "driving" ion such as Na+ or H+ to the flux of the substrate. The thermodynamics of such cyclical non-equilibrium systems are well understood and recent work has focused on the molecular mechanism of secondary active transport. The fact that these transporters change their conformation between an inward-facing and outward-facing conformation in a cyclical fashion, called the alternating access model, is broadly recognized as the molecular framework in which to describe transporter function. However, only with the advent of high resolution crystal structures and detailed computer simulations has it become possible to recognize common molecular-level principles between disp...
Na+/H+ exchangers catalyse an ion-exchange activity that is carried out in most, if not all cells... more Na+/H+ exchangers catalyse an ion-exchange activity that is carried out in most, if not all cells. SLC9B2, also known as NHA2, correlates with the long-sought after sodium/lithium (Na+/Li+) exchanger linked to the pathogenesis of diabetes mellitus and essential hypertension in humans. Despite its functional importance, structural information and the molecular basis of its ion-exchange mechanism have been lacking. Here, we report the cryo EM structures of bison NHA2 in detergent and in nanodiscs at 3.0 and 3.5 Å resolution, respectively. NHA2 shares closest structural similarity to the bacterial electrogenic Na+/H+ antiporter NapA, rather than other mammalian SLC9A members. Nevertheless, SSM-based electrophysiology results with NHA2 show the catalysis of electroneutral rather than electrogenic ion exchange, and the ion-binding site is quite distinctive, with a tryptophan-arginine- glutamate triad separated from the well-established ion-binding aspartates. These triad residues fine-tu...
In the biomolecular simulation (BMS) community, classical molecular dynamics (MD) simulations ena... more In the biomolecular simulation (BMS) community, classical molecular dynamics (MD) simulations enable the elucidation of the relationship between the structure of biomolecules such as proteins, nucleic acids, or lipids and their function via their dynamics. MD simulations account for approximately one quarter of the service units used on XSEDE resources. Although traditionally the generation of the data has been the computational bottleneck and has been highly optimized, more and more the analysis of the data is becoming a rate limiting step. Within the NSF DIBBs SPIDAL project we have been working on leveraging HPC resources for the analysis of BMS data [1], starting from two widely adopted software packages in the community, cpptraj [2] and MDAnalysis [3,4].
Currently, computation of the distance_array and rmsd for each frame in a molecular dynamics traj... more Currently, computation of the distance_array and rmsd for each frame in a molecular dynamics trajectory in MDAnalysis is a computationally intensive process. MDAnalysis (mdanalysis.org) is an open source library that allows for the analysis of molecular dynamics simulations. The goal of this REU was to speed up parts of MDAnalysis. We created a GPU based program through PyCUDA that allows us to compute distance arrays. PyCUDA (https:// mathema.tician.de/software/pycuda/) is a package that allows us to access NVIDIA’s CUDA API via python. Unfortunately, even though that it was evident that GPU’s do compute distance arrays faster than CPU’s, the transfer time between the local memory and the GPU is long enough such CPU computation is still faster. We also made slight modifications to the rmsd calculations to improve speeds by up to 30%.
Molecular dynamics (MD) computer simulations help elucidate details of the molecular processes in... more Molecular dynamics (MD) computer simulations help elucidate details of the molecular processes in complex biological systems, from protein dynamics to drug discovery. One major issue is that these MD simulation files are now commonly terabytes in size, which means analyzing the data from these files becomes a painstakingly expensive task. In the age of national supercomputers, methods of parallel analysis are becoming a necessity for the efficient use of time and high performance computing (HPC) resources but for any approach to parallel analysis, simply reading the file from disk becomes the performance bottleneck that limits overall analysis speed. One promising way around this file I/O hurdle is to use a parallel message passing interface (MPI) implementation with the HDF5 (Hierarchical Data Format 5) file format to access a single file simultaneously with numerous processes on a parallel file system. Our previous feasibility study suggested that this combination can lead to favo...
Na+/H+ exchangers catalyse an ion-exchange activity that is carried out in most, if not all cells... more Na+/H+ exchangers catalyse an ion-exchange activity that is carried out in most, if not all cells. SLC9B2, also known as NHA2, correlates with the long-sought after sodium/lithium (Na+/Li+) exchanger linked to the pathogenesis of diabetes mellitus and essential hypertension in humans. Despite its functional importance, structural information and the molecular basis of its ion-exchange mechanism have been lacking. Here, we report the cryo EM structures of bison NHA2 in detergent and in nanodiscs at 3.0 and 3.5 Å resolution, respectively. NHA2 shares closest structural similarity to the bacterial electrogenic Na+/H+ antiporter NapA, rather than other mammalian SLC9A members. Nevertheless, SSM-based electrophysiology results with NHA2 show the catalysis of electroneutral rather than electrogenic ion exchange, and the ion-binding site is quite distinctive, with a tryptophan-arginine- glutamate triad separated from the well-established ion-binding aspartates. These triad residues fine-tu...
To what extent must a hydrophobic gate expand for the channel to count as open? We address this q... more To what extent must a hydrophobic gate expand for the channel to count as open? We address this question using the nicotinic acetylcholine receptor (nAChR) as the exemplar. The nAChR is an integral membrane protein which forms a cation selective channel gated by neurotransmitter binding to its extracellular domain. A hydrophobic gating model has been proposed for the nAChR, whereby the pore is incompletely occluded in the closed state channel, with a narrow hydrophobic central gate region which presents an energetic barrier to ion permeation. The nAChR pore is lined by a parallel bundle of five M2 alpha-helices, with the gate formed by three rings of hydrophobic sidechains (9', 13', and 17' of M2). A number of models have been proposed to describe the nature of the conformational change underlying the closed to open transition of the nAChR. These models involve different degrees of M2 helix displacement, rotation, and/or kinking. In this study, we use a simple pore expan...
Analysis of molecular dynamics (MD) trajectories is becoming more and more challenging with simul... more Analysis of molecular dynamics (MD) trajectories is becoming more and more challenging with simulation times routinely exceeding microseconds (with millions of frames) and increasing in size (with millions of particles). The MDAnalysis library (http://mdanalysis.org) is a versatile open source package that provides a foundation for analysing trajectories, with a particular emphasis on biomolecular simulations. In order to improve MDAnalysis for large simulations, we developed a set of non-trivial benchmarking systems of variable sizes. We generated a modular library of lipid vesicles with the coarse-grained Dry Martini force field, ranging in size from 10 nm to 30 nm radius. These vesicles can be combined in larger multi-vesicle systems in order to produce a range of benchmark systems with variable particle numbers. The systems will also allow us to address the question under which conditions vesicles fuse. We generated simulation systems with up to six vesicles and 3.5 million part...
We predicted water-octanol partition coefficients for the molecules in the SAMPL7 challenge with ... more We predicted water-octanol partition coefficients for the molecules in the SAMPL7 challenge with explicit solvent classical molecular dynamics (MD) simulations. Water hydration free energies and octanol solvation free energies were calculated with a windowed alchemical free energy approach. Three commonly used force fields (AMBER GAFF, CHARMM CGenFF, OPLS-AA) were tested. Special emphasis was placed on converging all simulations, using a criterion developed for the SAMPL6 challenge. In aggregate, over 1000 μ\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\mu$$\end{document}s of simulations were performed, with some free energy windows remaining not fully converged even after 1 μ\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\mu$$\end{document}s of simulation time. Nevertheless, the amount of sampling produced logPow\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\log P_{ow}$$\end{document} estimates with a precision of 0.1 log units or better for converged simulations. Despite being probably as fully sampled as can expected and is feasible, the agreement with experiment remained modest for all force fields, with no force field performing better than 1.6 in root mean squared error. Overall, our results indicate that a large amount of sampling is necessary to produce precise logPow\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\log P_{ow}$$\end{document} predictions for the SAMPL7 compounds and that high precision does not necessarily lead to high accuracy. Thus, fundamental problems remain to be solved for physics-based logPow\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\log P_{ow}$$\end{document} predictions.
YiiP is a secondary transporter that couples Zn2+ transport to the proton motive force. Structura... more YiiP is a secondary transporter that couples Zn2+ transport to the proton motive force. Structural studies of YiiP from prokaryotes as well as Znt8 from humans revealed three different Zn2+ sites and a conserved homodimeric architecture. These structures define the inward-facing and outward-facing states that characterize the archetypal alternating access mechanism of transport. To study effects of Zn2+ binding on the conformational transition, we have used a YiiP/Fab complex for single-particle cryo-EM together with Molecular Dynamics simulation to compare structures of YiiP from S. oneidensis in presence and absence of Zn2+. Without Zn2+, YiiP exhibits enhanced flexibility and adopts a novel conformation that appears to be an intermediate state. The transition closes a hydrophobic gate and is controlled by the Zn2+ site at the cytoplasmic membrane interface. This work enhances our understanding of individual Zn2+ binding sites and their role in the conformational dynamics that gov...
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