All-Atom Molecular Dynamics Simulations

With increasing computational power (aka GPU) that can be accessed these days, it is no wonder that performing all-atom molecular dynamics simulation for a longer time, with duplicates and/or triplicates, has become easier.

Two publications report all-atom MD data that have significant implication in two diverse areas. The first one is the popular CRISPR-Cas9 system and the second one is Dengue virus.

With these data it should pave way for more insights.

CRISPR-Cas9 all atom simulation (total of 400-600ns data)
Zuo Z, & Liu J (2016). Cas9-catalyzed DNA Cleavage Generates Staggered Ends: Evidence from Molecular Dynamics Simulations. Scientific reports, 5 PMID: 27874072

Entire Dengue viral envelope complex simluation (1 microsecond data)
Marzinek JK, Holdbrook DA, Huber RG, Verma C, & Bond PJ (2016). Pushing the Envelope: Dengue Viral Membrane Coaxed into Shape by Molecular Simulations. Structure (London, England : 1993), 24 (8), 1410-20 PMID: 27396828

References:

1. https://www.sciencedaily.com/releases/2017/01/170111131105.htm
2. http://www.research.a-star.edu.sg/research/7645/molecular-movie-reels-viral-envelope-into-shape

Computational Tools from Biophysical Journal

Wanted to share this exciting news with you! Biophysical Journal has created a collection of papers that describe tools and software that can be routinely used in biological research. Editor Prof. Leslie Loew mentions that the full-text of articles in this collection will be freely available until February 25, 2016.

…a year agoBiophysical Journal called for papers in a new class of articles called Computational Tools (CTs). These papers are limited to five pages in length and describe software for analysis of experimental data, modeling and/or simulation, or database services. All are required to be freely accessible and open to the research community. In addition to following the usual review criteria of novelty and importance, reviewers of CTs are asked to test drive the software and judge its usability.

Among the thirteen, some of them are directly related to Structural Biology and Bioinformatics. So, here’s my “curated” list.

Article Title
CHARMM-GUI HMMM Builder for Membrane Simulations with the Highly Mobile Membrane-Mimetic Model

Weblink: http://www.charmm-gui.org/input/hmmm

Abstract
Slow diffusion of the lipids in conventional all-atom simulations of membrane systems makes it difficult to sample large rearrangements of lipids and protein-lipid interactions. Recently, Tajkhorshid and co-workers developed the highly mobile membrane-mimetic (HMMM) model with accelerated lipid motion by replacing the lipid tails with small organic molecules. The HMMM model provides accelerated lipid diffusion by one to two orders of magnitude, and is particularly useful in studying membrane-protein associations. However, building an HMMM simulation system is not easy, as it requires sophisticated treatment of the lipid tails. In this study, we have developed CHARMM-GUI HMMM Builder (http://www.charmm-gui.org/input/hmmm) to provide users with ready-to-go input files for simulating HMMM membrane systems with/without proteins. Various lipid-only and protein-lipid systems are simulated to validate the qualities of the systems generated by HMMM Builder with focus on the basic properties and advantages of the HMMM model. HMMM Builder supports all lipid types available in CHARMM-GUI and also provides a module to convert back and forth between an HMMM membrane and a full-length membrane. We expect HMMM Builder to be a useful tool in studying membrane systems with enhanced lipid diffusion.

Article Title
MDTraj: A Modern Open Library for the Analysis of Molecular Dynamics Trajectories

Weblink: http://mdtraj.org/latest/

Abstract
As molecular dynamics (MD) simulations continue to evolve into powerful computational tools for studying complex biomolecular systems, the necessity of flexible and easy-to-use software tools for the analysis of these simulations is growing. We have developed MDTraj, a modern, lightweight, and fast software package for analyzing MD simulations. MDTraj reads and writes trajectory data in a wide variety of commonly used formats. It provides a large number of trajectory analysis capabilities including minimal root-mean-square-deviation calculations, secondary structure assignment, and the extraction of common order parameters. The package has a strong focus on interoperability with the wider scientific Python ecosystem, bridging the gap between MD data and the rapidly growing collection of industry-standard statistical analysis and visualization tools in Python. MDTraj is a powerful and user-friendly software package that simplifies the analysis of MD data and connects these datasets with the modern interactive data science software ecosystem in Python.

Article Title
MDN: A Web Portal for Network Analysis of Molecular Dynamics Simulations

Weblink: http://mdn.cheme.columbia.edu/

Abstract
We introduce a web portal that employs network theory for the analysis of trajectories from molecular dynamics simulations. Users can create protein energy networks following methodology previously introduced by our group, and can identify residues that are important for signal propagation, as well as measure the efficiency of signal propagation by calculating the network coupling. This tool, called MDN, was used to characterize signal propagation in Escherichia coli heat-shock protein 70-kDa. Two variants of this protein experimentally shown to be allosterically active exhibit higher network coupling relative to that of two inactive variants. In addition, calculations of partial coupling suggest that this quantity could be used as part of the criteria to determine pocket druggability in drug discovery studies.

Article Title
Multidomain Assembler (MDA) Generates Models of Large Multidomain Proteins

Weblink: http://www.rbvi.ucsf.edu/chimera/docs/UsersGuide/midas/mda.html AND http://www.cell.com/biophysj/biophysj/supplemental/S0006-3495(15)00339-2

Abstract
Homology modeling predicts protein structures using known structures of related proteins as templates. We developed MULTIDOMAIN ASSEMBLER (MDA) to address the special problems that arise when modeling proteins with large numbers of domains, such as fibronectin with 30 domains, as well as cases with hundreds of templates. These problems include how to spatially arrange nonoverlapping template structures, and how to get the best template coverage when some sequence regions have hundreds of available structures while other regions have a few distant homologs. MDA automates the tasks of template searching, visualization, and selection followed by multidomain model generation, and is part of the widely used molecular graphics package UCSF CHIMERA (University of California, San Francisco). We demonstrate applications and discuss MDA’s benefits and limitations.

Article Title
RedMDStream: Parameterization and Simulation Toolbox for Coarse-Grained Molecular Dynamics Models

Weblink: https://bionano.cent.uw.edu.pl/Software/RedMD

Abstract
Coarse-grained (CG) models in molecular dynamics (MD) are powerful tools to simulate the dynamics of large biomolecular systems on micro- to millisecond timescales. However, the CG model, potential energy terms, and parameters are typically not transferable between different molecules and problems. So parameterizing CG force fields, which is both tedious and time-consuming, is often necessary. We present RedMDStream, a software for developing, testing, and simulating biomolecules with CG MD models. Development includes an automatic procedure for the optimization of potential energy parameters based on metaheuristic methods. As an example we describe the parameterization of a simple CG MD model of an RNA hairpin.

Article Title
A Web Interface for Easy Flexible Protein-Protein Docking with ATTRACT

Weblink: http://www.attract.ph.tum.de/services/ATTRACT/attract.html

Abstract
Protein-protein docking programs can give valuable insights into the structure of protein complexes in the absence of an experimental complex structure. Web interfaces can facilitate the use of docking programs by structural biologists. Here, we present an easy web interface for protein-protein docking with the ATTRACT program. While aimed at nonexpert users, the web interface still covers a considerable range of docking applications. The web interface supports systematic rigid-body protein docking with the ATTRACT coarse-grained force field, as well as various kinds of protein flexibility. The execution of a docking protocol takes up to a few hours on a standard desktop computer.

Article Title
ReaDDyMM: Fast Interacting Particle Reaction-Diffusion Simulations Using Graphical Processing Units

Weblink: https://github.com/readdy

Abstract
ReaDDy is a modular particle simulation package combining off-lattice reaction kinetics with arbitrary particle interaction forces. Here we present a graphical processing unit implementation of ReaDDy that employs the fast multiplatform molecular dynamics package OpenMM. A speedup of up to two orders of magnitude is demonstrated, giving us access to timescales of multiple seconds on single graphical processing units. This opens up the possibility of simulating cellular signal transduction events while resolving all protein copies.

Article Title
Local Perturbation Analysis: A Computational Tool for Biophysical Reaction-Diffusion Models

Weblink: http://www.cell.com/biophysj/biophysj/supplemental/S0006-3495(14)04670-0

Abstract
Diffusion and interaction of molecular regulators in cells is often modeled using reaction-diffusion partial differential equations. Analysis of such models and exploration of their parameter space is challenging, particularly for systems of high dimensionality. Here, we present a relatively simple and straightforward analysis, the local perturbation analysis, that reveals how parameter variations affect model behavior. This computational tool, which greatly aids exploration of the behavior of a model, exploits a structural feature common to many cellular regulatory systems: regulators are typically either bound to a membrane or freely diffusing in the interior of the cell. Using well-documented, readily available bifurcation software, the local perturbation analysis tracks the approximate early evolution of an arbitrarily large perturbation of a homogeneous steady state. In doing so, it provides a bifurcation diagram that concisely describes various regimes of the model’s behavior, reducing the need for exhaustive simulations to explore parameter space. We explain the method and provide detailed step-by-step guides to its use and application.

References:

1. http://www.cell.com/biophysj/collections/computational-tools
2. Qi Y, Cheng X, Lee J, Vermaas JV, Pogorelov TV, Tajkhorshid E, Park S, Klauda JB, & Im W (2015). CHARMM-GUI HMMM Builder for Membrane Simulations with the Highly Mobile Membrane-Mimetic Model. Biophysical journal, 109 (10), 2012-22 PMID: 26588561
3. McGibbon RT, Beauchamp KA, Harrigan MP, Klein C, Swails JM, Hernández CX, Schwantes CR, Wang LP, Lane TJ, & Pande VS (2015). MDTraj: A Modern Open Library for the Analysis of Molecular Dynamics Trajectories. Biophysical journal, 109 (8), 1528-32 PMID: 26488642
4. Ribeiro AA, & Ortiz V (2015). MDN: A Web Portal for Network Analysis of Molecular Dynamics Simulations. Biophysical journal, 109 (6), 1110-6 PMID: 26143656
5. Hertig S, Goddard TD, Johnson GT, & Ferrin TE (2015). Multidomain Assembler (MDA) Generates Models of Large Multidomain Proteins. Biophysical journal, 108 (9), 2097-102 PMID: 25954868
6. Leonarski F, & Trylska J (2015). RedMDStream: Parameterization and Simulation Toolbox for Coarse-Grained Molecular Dynamics Models. Biophysical journal, 108 (8), 1843-7 PMID: 25902423
7. de Vries SJ, Schindler CE, Chauvot de Beauchêne I, & Zacharias M (2015). A web interface for easy flexible protein-protein docking with ATTRACT. Biophysical journal, 108 (3), 462-5 PMID: 25650913
8. Biedermann J, Ullrich A, Schöneberg J, & Noé F (2015). ReaDDyMM: Fast interacting particle reaction-diffusion simulations using graphical processing units. Biophysical journal, 108 (3), 457-61 PMID: 25650912
9. Holmes WR, Mata MA, & Edelstein-Keshet L (2015). Local perturbation analysis: a computational tool for biophysical reaction-diffusion models. Biophysical journal, 108 (2), 230-6 PMID: 25606671

Prions – From Dr. Jekyll to being Mr. Hyde

Image reproduced under Creative Commons licence. Source: Wikimedia commons

The Cellular Prion Protein (PrP^c) like Dr. Jekyll converts into PrP^Sc , a fatal conformational form, like Mr. Hyde, and is responsible for a variety of neurodegenrative disorders. Unlike the use of a potion, this molecular Jekyll and Hyde undergoes conformational change in low pH environment, such as in endosomes. While, there has been many studies done in the past of how this conformational change happens,  a recent paper has tried to list the structural and dynamic properties using Molecular Dynamics.

To list these properties,three structures were taken into consideration; one NMR structure (PDB id: 1QLX) and two X-ray structures (PDB id: 2W9E and 3HAK). Interestingly the 3HAK structure is from a SNP variant of human PrPc, where the Met129 is replaced by Val129. Furthermore, those who genetically have this variant are less susceptible to Prion diseases!

Structural alignment of 1QLX (blue), 2W9E (red), and 3HAK (orange) with Met129/Val129 shown as sticks. Image made using PyMOL

Using an in-house MD package called in lucem molecular mechanics, ilmm for short, Chen et al simulated the three structures under two different pH conditions (pH 5 and pH 7) and under two different temperatures (298K/25C and 310K/37C), totaling for about 3.6 microseconds of simulation. (For each structure under each condition the MD simulation was performed in triplicates.)

Analyzing the MD results they found that at 37C and low pH the C-terminal globular domain had significant destabilization effects.

• The helix HA and its neighboring loop S1-HA for the SNP variant was higher compared to other two structures at 37C and low pH. It is interesting to note that the S1-HA loop becomes a strand during the prion’s conversion.
• At low pH, another helix HB destabilizes, where the His187 becomes solvent exposed, leading to partial unfolding of the C-terminus.
• Two residues, Phe198 and Met134, converting from being part of the hydrophobic core to being exposed to the solvent may be involved in partial unfolding and might possibly provide aggregation sites.
• The X-loop in the Val129 SNP variant’s structure took a different conformation that was not populated by the other two structures.
• Formation of new secondary structures of the N-terminus region to either alpha and beta strands is spontaneous. While, in all two structures both alpha and beta strands formation was seen, in the SNP variant alpha strands were rarely formed. (This N-terminus region is missing from the solved structures and hence was modeled and in each starting structure this region was unstructured.)

These results give more insights into the conversion of the benign form of human Prion to the infectious form.

References:

1. Chen, W., van der Kamp, M., & Daggett, V. (2014). Structural and Dynamic Properties of the Human Prion Protein Biophysical Journal, 106 (5), 1152-1163 DOI: 10.1016/j.bpj.2013.12.053

Molecular Dynamics and Pest Control

PDBid:3RIF. Image made using PyMOL

How can Molecular Dynamics help in controlling pests? Well, insects have something called resistant to dieldrin receptor or RDL receptors. These are part of a big family of receptors called Cys-loop receptors. Insecticides invariably bind to these receptors and in turn affect the neurotransmission in the pest. So, it becomes imperative to understand these receptors in order to develop and rationally design insecticides that are highly specific.

Molecular Dynamics are part and parcel of the toolkit for a structural bioinformatician. Whether it is for relaxing a structure or for analyzing complex stuff. Most often, they are used in scenarios where a single amino acid mutation is made in the protein. Coupled it with homology modeling and docking the picture gets perfect.

Ashby et al published their work that incorporates MD, Homology modeling and docking studies to the RDL receptor. The most often used rules in homology modeling are “Alignment, Alignment, Alignment”, and when the sequence identity to the closest invertebrate homolog for RDL receptor is 38.1% it definitely raises a flag/concern. That’s most likely the place MD plays a role in relaxing the structure. Moreover, MD done after ligand docking to a homology modeled structure resolves, to a large extent, the noise/false positives that the prediction methods incorporate. This strategy is useful when ligand bound x-ray structures are hard to obtain due to many reasons. And, this has been the approach for the study published by Ashby et al.

Using this approach, conserved residues that contribute towards GABA binding were confirmed, and also other residues’ role in binding were found. When the significance of these residues were found via multiple MD simulations, mutagenesis studies confirmed their role in specific binding.

Thus, combining previously known functional data, mutagenesis, and simulation (MD and docking) data the residues R111, E204, F206, Y254, and R256 were identified to be highly critical for the activity of RDL receptor. Now, this new study definitely will be giving jitters to the pest!

Reference:

Ashby, J., McGonigle, I., Price, K., Cohen, N., Comitani, F., Dougherty, D., Molteni, C., & Lummis, S. (2012). GABA Binding to an Insect GABA Receptor: A Molecular Dynamics and Mutagenesis Study Biophysical Journal, 103 (10), 2071-2081 DOI: 10.1016/j.bpj.2012.10.016