| 1. |
- Irrgang, M Eric, et al.
(författare)
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gmxapi : a high-level interface for advanced control and extension of molecular dynamics simulations.
- 2018
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Ingår i: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 34:22, s. 3945-3947
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Tidskriftsartikel (refereegranskat)abstract
- Summary: Molecular dynamics simulations have found use in a wide variety of biomolecular applications, from protein folding kinetics to computational drug design to refinement of molecular structures. Two areas where users and developers frequently need to extend the built-in capabilities of most software packages are implementing custom interactions, for instance biases derived from experimental data, and running ensembles of simulations. We present a Python high-level interface for the popular simulation package GROMACS that 1) allows custom potential functions without modifying the simulation package code, 2) maintains the optimized performance of GROMACS, and 3) presents an abstract interface to building and executing computational graphs that allows transparent low-level optimization of data flow and task placement. Minimal dependencies make this integrated API for the GROMACS simulation engine simple, portable, and maintainable. We demonstrate this API for experimentally-driven refinement of protein conformational ensembles.Availability: LGPLv2.1 source and instructions are available at https://github.com/kassonlab/gmxapi.Supplementary information: Supplementary data are available at Bioinformatics online.
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| 2. |
- Crean, Rory M., et al.
(författare)
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KIF-Key Interactions Finder : A program to identify the key molecular interactions that regulate protein conformational changes
- 2023
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Ingår i: Journal of Chemical Physics. - : American Institute of Physics (AIP). - 0021-9606 .- 1089-7690. ; 158:14
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Tidskriftsartikel (refereegranskat)abstract
- Simulation datasets of proteins (e.g., those generated by molecular dynamics simulations) are filled with information about how a non-covalent interaction network within a protein regulates the conformation and, thus, function of the said protein. Most proteins contain thousands of non-covalent interactions, with most of these being largely irrelevant to any single conformational change. The ability to automatically process any protein simulation dataset to identify non-covalent interactions that are strongly associated with a single, defined conformational change would be a highly valuable tool for the community. Furthermore, the insights generated from this tool could be applied to basic research, in order to improve understanding of a mechanism of action, or for protein engineering, to identify candidate mutations to improve/alter the functionality of any given protein. The open-source Python package Key Interactions Finder (KIF) enables users to identify those non-covalent interactions that are strongly associated with any conformational change of interest for any protein simulated. KIF gives the user full control to define the conformational change of interest as either a continuous variable or categorical variable, and methods from statistics or machine learning can be applied to identify and rank the interactions and residues distributed throughout the protein, which are relevant to the conformational change. Finally, KIF has been applied to three diverse model systems (protein tyrosine phosphatase 1B, the PDZ3 domain, and the KE07 series of Kemp eliminases) in order to illustrate its power to identify key features that regulate functionally important conformational dynamics.
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| 3. |
- Giraldo, Ana M. Villamil, et al.
(författare)
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Measuring single-virus fusion kinetics using an assay for nucleic acid exposure
- 2022
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Ingår i: Biophysical Journal. - : Elsevier. - 0006-3495 .- 1542-0086. ; 121:23, s. 4467-4475
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Tidskriftsartikel (refereegranskat)abstract
- The kinetics by which individual enveloped viruses fuse with membranes provide an important window into viral-entry mechanisms. We have developed a real-time assay using fluorescent probes for single-virus genome exposure than can report on stages of viral entry including or subsequent to fusion pore formation and prior to viral genome trafficking. We accom-plish this using oxazole yellow nucleic-acid-binding dyes, which can be encapsulated in the lumen of target membranes to permit specific detection of fusion events. Since increased fluorescence of the dye occurs only when it encounters viral genome via a fusion pore and binds, this assay excludes content leakage without fusion. Using this assay, we show that influenza virus fuses with liposomes of different sizes with indistinguishable kinetics by both testing liposomes extruded through pores of different radii and showing that the fusion kinetics of individual liposomes are uncorrelated with the size of the liposome. These results suggest that the starting curvature of such liposomes does not control the rate-limiting steps in influenza entry.
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| 4. |
- Hays, Jennifer M., et al.
(författare)
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Inference of Joint Conformational Distributions from Separately Acquired Experimental Measurements
- 2021
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Ingår i: The Journal of Physical Chemistry Letters. - : American Chemical Society (ACS). - 1948-7185. ; 12:6, s. 1606-1611
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Tidskriftsartikel (refereegranskat)abstract
- Flexible proteins serve vital roles in a multitude of biological processes. However, determining their full conformational ensembles is extremely difficult because this requires detailed knowledge about the heterogeneity of the protein's degrees of freedom. Label-based experiments such as double electron-electron resonance (DEER) are very useful in studying flexible proteins, as they provide distributional data on heterogeneity. These experiments are typically performed separately, so information about correlation between distributions is lost. We have developed a method to recover correlation information using nonequilibrium work estimates in molecular dynamics refinement. We tested this method on a simple model of an alternating-access transporter for which the true joint distributions are known, and it successfully recovered the true joint distribution. We also applied our method to the protein syntaxin-1a, where it discarded physically implausible conformations. Our method thus provides a way to recover correlation structure in separate experimental measurements of conformational ensembles and refines the resulting structural ensemble.
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| 5. |
- Hays, Jennifer M., et al.
(författare)
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Refinement of highly flexible protein structures using simulation-guided spectroscopy
- 2018
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Ingår i: Angewandte Chemie International Edition. - : John Wiley & Sons. - 1433-7851 .- 1521-3773. ; 57:52, s. 17110-17114
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Tidskriftsartikel (refereegranskat)abstract
- Highly flexible proteins present a special challenge for structure determination because they are multi-structured yet not disordered, so their conformational ensembles are essential for understanding function. Because spectroscopic measurements of multiple conformational populations often provide sparse data, experiment selection is a limiting factor in conformational refinement. We have developed an approach using molecular simulations and information theory to select which experiments best refine conformational ensembles. We test this approach on three flexible proteins. For proteins where a clear mechanistic hypothesis exists, we systematically identify experiments that test this hypothesis. When available data do not yield such mechanistic hypotheses, we identify experiments that significantly outperform structure-guided approaches in conformational refinement. Our approach offers a particular advantage when refining challenging, underdetermined protein conformational ensembles.
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| 6. |
- Irrgang, M. Eric, et al.
(författare)
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gmxapi : A GROMACS-native Python interface for molecular dynamics with ensemble and plugin support
- 2022
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Ingår i: PloS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 18:2
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Tidskriftsartikel (refereegranskat)abstract
- Gmxapi provides an integrated, native Python API for both standard and advanced molecular dynamics simulations in GROMACS. The Python interface permits multiple levels of integration with the core GROMACS libraries, and legacy support is provided via an interface that mimics the command-line syntax, so that all GROMACS commands are fully available. Gmxapi has been officially supported since the GROMACS 2019 release and is enabled by default in current versions of the software. Here we describe gmxapi 0.3 and later. Beyond simply wrapping GROMACS library operations, the API permits several advanced operations that are not feasible using the prior command-line interface. First, the API allows custom user plugin code within the molecular dynamics force calculations, so users can execute custom algorithms without modifying the GROMACS source. Second, the Python interface allows tasks to be dynamically defined, so high-level algorithms for molecular dynamics simulation and analysis can be coordinated with loop and conditional operations. Gmxapi makes GROMACS more accessible to custom Python scripting while also providing support for high-level data-flow simulation algorithms that were previously feasible only in external packages. Author summaryThe gmxapi software provides a Python interface for molecular dynamics simulations in GROMACS. In addition to simply wrapping GROMACS commands, it supports custom user plugin code, ensemble simulation, and data-flow chaining of commands. As such, gmxapi enables the writing and execution of high-level simulation algorithms. The software ships with GROMACS and is freely available under an LGPL2 license.
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| 7. |
- Liao, Qinghua, et al.
(författare)
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Long Time-Scale Atomistic Simulations of the Structure and Dynamics of Transcription Factor-DNA Recognition
- 2019
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 123:17, s. 3576-3590
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Tidskriftsartikel (refereegranskat)abstract
- Recent years have witnessed an explosion of interest in computational studies of DNA binding proteins, including both coarse grained and atomistic simulations of transcription factor-DNA recognition, to understand how these transcription factors recognize their binding sites on the DNA with such exquisite specificity. The present study performs microsecond time scale all-atom simulations of the dimeric form of the lactose repressor (Lad), both in the absence of any DNA and in the presence of both specific and nonspecific complexes, considering three different DNA sequences. We examine, specifically, the conformational differences between specific and nonspecific protein DNA interactions, as well as the behavior of the helix-turn-helix motif of Lad when interacting with the DNA. Our simulations suggest that stable Lad binding occurs primarily to bent A-form DNA, with a loss of Lad conformational entropy and optimization of correlated conformational equilibria across the protein. In addition, binding to the specific operator sequence involves a slightly larger number of stabilizing DNA protein hydrogen bonds (in comparison to nonspecific complexes), which may account for the experimentally observed specificity for this operator. In doing so, our simulations provide a detailed atomistic description of potential structural drivers for LacI selectivity.
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| 8. |
- Mannsverk, Steinar, et al.
(författare)
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Influenza Virus Membrane Fusion Is Promoted by the Endosome-Resident Phospholipid Bis(monoacylglycero)phosphate
- 2022
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 126:49, s. 10445-10451
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Tidskriftsartikel (refereegranskat)abstract
- The phospholipid bis(monoacylglycero)phosphate (BMP) is enriched in late endosomal and endolysosomal membranes and is believed to be involved in membrane deformation and generation of intralumenal vesicles within late endosomes. Previous studies have demonstrated that BMP promotes membrane fusion of several enveloped viruses, but a limited effect has been found on influenza virus. Here, we report the use of single-virus fusion assays to dissect BMP's effect on influenza virus fusion in greater depth. In agreement with prior reports, we found that hemifusion kinetics and efficiency were unaffected by the addition of 10-20 mol % BMP to the target membrane. However, using an assay for fusion pore formation and genome exposure, we found full fusion efficiency to be substantially enhanced by the addition of 10-20 mol % BMP to the target membrane, while the kinetics remained unaffected. By comparing BMP to other negatively charged phospholipids, we found the effect on fusion efficiency mainly attributable to headgroup charge, although we also hypothesize a role for BMP's unusual chemical structure. Our results suggest that BMP function as a permissive factor for a wider range of viruses than previously reported. We hypothesize that BMP may be a general cofactor for endosomal entry of enveloped viruses.
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| 9. |
- Rawle, Robert J., et al.
(författare)
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Detecting and Controlling Dye Effects in Single-Virus Fusion Experiments
- 2019
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Ingår i: Biophysical Journal. - : CELL PRESS. - 0006-3495 .- 1542-0086. ; 117:3, s. 445-452
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Tidskriftsartikel (refereegranskat)abstract
- Fluorescent dye-dequenching assays provide a powerful and versatile means to monitor membrane fusion events. They have been used in bulk assays, for measuring single events in live cells, and for detailed analysis of fusion kinetics for liposomal, viral, and cellular fusion processes; however, the dyes used also have the potential to perturb membrane fusion. Here, using single-virus measurements of influenza membrane fusion, we show that fluorescent membrane probes can alter both the efficiency and the kinetics of lipid mixing in a dye- and illumination-dependent manner. R18, a dye that is commonly used to monitor lipid mixing between membranes, is particularly prone to these effects, whereas Texas Red is somewhat less sensitive. R18 further undergoes photoconjugation to viral proteins in an illumination-dependent manner that correlates with its inactivation of viral fusion. These results demonstrate how fluorescent probes can perturb measurements of biological activity and provide both data and a method for determining minimally perturbative measurement conditions.
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| 10. |
- Yehorova, Dariia, et al.
(författare)
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Key interaction networks : Identifying evolutionarily conserved non-covalent interaction networks across protein families
- 2024
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Ingår i: Protein Science. - : John Wiley & Sons. - 0961-8368 .- 1469-896X. ; 33:3
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Tidskriftsartikel (refereegranskat)abstract
- Protein structure (and thus function) is dictated by non-covalent interaction networks. These can be highly evolutionarily conserved across protein families, the members of which can diverge in sequence and evolutionary history. Here we present KIN, a tool to identify and analyze conserved non-covalent interaction networks across evolutionarily related groups of proteins. KIN is available for download under a GNU General Public License, version 2, from https://www.github.com/kamerlinlab/KIN. KIN can operate on experimentally determined structures, predicted structures, or molecular dynamics trajectories, providing insight into both conserved and missing interactions across evolutionarily related proteins. This provides useful insight both into protein evolution, as well as a tool that can be exploited for protein engineering efforts. As a showcase system, we demonstrate applications of this tool to understanding the evolutionary-relevant conserved interaction networks across the class A β-lactamases.
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