The ugly, bad, and good stories of large-scale biomolecular simulations

Gupta, Chitrak; Sarkar, Daipayan; Tieleman, D. Peter; Singharoy, Abhishek

doi:10.1016/j.sbi.2022.102338

Cited by 47 publications

(47 citation statements)

References 42 publications

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“…Recent years have seen increased interest in characterizing the quinary structure of proteins, 75, 76 which refers to the specific sticking interactions that cause the cytosol to demix and enable particular sets of proteins to have higher local concentrations and adopt preferential orientations with respect to one another. Exascale computing has enabled molecular dynamics simulations to be conducted on systems approaching the size of cells, 77, 78 and with these “computational microscope” studies the structure of transient protein assemblies in a cellular milieu are coming into focus. To date however, there are few experimental techniques that can measure quinary interactions to test the predictions from computational microscopy.…”

Section: Discussionmentioning

confidence: 99%

Proteome-Wide Photo-Crosslinking Enables Residue-Level Visualization of Protein Interaction Networks in vivo

Faustino

Sharma

Yadav

et al. 2022

Preprint

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Crosslinking mass spectrometry (XL-MS) is emerging as a unique method at the crossroads of structural and cellular biology, uniquely capable of identifying protein-protein interactions with residue-level resolution and on the proteome-wide scale. With the development of crosslinkers that can form linkages inside cells and easily cleave during fragmentation on the mass spectrometer (MS-cleavable crosslinks), it has become increasingly facile to identify contacts between any two proteins in complex samples, including in live cells or tissues. Photo-crosslinkers possess the advantages of high temporal resolution and high reactivity, thereby engaging all residue-types (rather than just lysine); nevertheless, photo-crosslinkers have not enjoyed widespread use, and have yet to be employed for proteome-wide studies, because their products are challenging to identify, and an MS-cleavable photo-crosslinker has not yet been reported. Here, we demonstrate the synthesis and application of two heterobifunctional photo-crosslinkers that feature diazirines and N-hydroxy-succinimidyl carbamate groups, the latter of which unveil MS-cleavable linkage upon acyl transfer to protein targets. Moreover, these crosslinkers demonstrate high water-solubility and cell-permeability. Using these compounds, we demonstrate the feasibility of proteome-wide photo-crosslinking mass spectrometry (photo-XL-MS), both in extracts and in cellulo. These studies provide a partial interaction map of the E. coli cytosol with residue-level resolution. We find that photo- XL-MS has a propensity to capture protein-protein interactions, particularly involving low- abundance uncharacterized proteins, suggesting it could be a powerful tool to shed light on the "darker" corners of the proteome. Overall, we describe methods that enable the detection of protein quinary interaction networks in their native environment at residue-level resolution proteome-wide, and we expect they will prove useful toward the effort to explore the molecular sociology of the cell.

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Section: Discussionmentioning

confidence: 99%

Proteome-Wide Photo-Crosslinking Enables Residue-Level Visualization of Protein Interaction Networks in vivo

Faustino

Sharma

Yadav

et al. 2022

Preprint

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“…However, the hope that, with a continuing increase in capacity, all processes could be captured with such detailed models turned out to be idle. Even today, with access to exascale computing power, all‐atom simulations are still limited to spatiotemporal scales less than 100 nm and typically covering few microseconds 3–5 . Considering the gap with processes in real life, the need for a CG description is still as urgent as in the early days 5–11 .…”

Section: Introductionmentioning

confidence: 99%

Two decades of Martini: Better beads, broader scope

Marrink

Monticelli

Melo

et al. 2022

WIREs Comput Mol Sci

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133

109

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The Martini model, a coarse-grained force field for molecular dynamics simulations, has been around for nearly two decades. Originally developed for lipidbased systems by the groups of Marrink and Tieleman, the Martini model has over the years been extended as a community effort to the current level of a general-purpose force field. Apart from the obvious benefit of a reduction in computational cost, the popularity of the model is largely due to the systematic yet intuitive building-block approach that underlies the model, as well as the open nature of the development and its continuous validation. The easy implementation in the widely used Gromacs software suite has also been instrumental. Since its conception in 2002, the Martini model underwent a gradual refinement of the bead interactions and a widening scope of applications. In this review, we look back at this development, culminating with the release of the Martini 3 version in 2021. The power of the model is illustrated with key examples of recent important findings in biological and material sciences enabled with Martini, as well as examples from areas where coarse-grained resolution is essential, namely highthroughput applications, systems with large complexity, and simulations approaching the scale of whole cells.

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“…For large values of N , say in the millions, such a calculation and more importantly its repeats become computationally prohibitive. While it is possible to design hardware that is specific to such calculations and while many efforts are underway to improve the software that implement them − (currently allowing for molecular dynamics simulations of systems with up to 100 million atoms − ), parallel efforts are put into developing simplified models in which the number of atoms is reduced to make the calculation more tractable. Of particular interest is to replace the explicit solvent with a potential of mean force that mimics its effect on the molecule.…”

Section: Introductionmentioning

confidence: 99%

Computing the Volume, Surface Area, Mean, and Gaussian Curvatures of Molecules and Their Derivatives

Koehl

Akopyan²,

Edelsbrunner

2023

J. Chem. Inf. Model.

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Geometry is crucial in our efforts to comprehend the structures and dynamics of biomolecules. For example, volume, surface area, and integrated mean and Gaussian curvature of the union of balls representing a molecule are used to quantify its interactions with the water surrounding it in the morphometric implicit solvent models. The Alpha Shape theory provides an accurate and reliable method for computing these geometric measures. In this paper, we derive homogeneous formulas for the expressions of these measures and their derivatives with respect to the atomic coordinates, and we provide algorithms that implement them into a new software package, AlphaMol. The only variables in these formulas are the interatomic distances, making them insensitive to translations and rotations. AlphaMol includes a sequential algorithm and a parallel algorithm. In the parallel version, we partition the atoms of the molecule of interest into 3D rectangular blocks, using a kd-tree algorithm. We then apply the sequential algorithm of AlphaMol to each block, augmented by a buffer zone to account for atoms whose ball representations may partially cover the block. The current parallel version of AlphaMol leads to a 20-fold speed-up compared to an independent serial implementation when using 32 processors. For instance, it takes 31 s to compute the geometric measures and derivatives of each atom in a viral capsid with more than 26 million atoms on 32 Intel processors running at 2.7 GHz. The presence of the buffer zones, however, leads to redundant computations, which ultimately limit the impact of using multiple processors. AlphaMol is available as an OpenSource software.

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The ugly, bad, and good stories of large-scale biomolecular simulations

Cited by 47 publications

References 42 publications

Proteome-Wide Photo-Crosslinking Enables Residue-Level Visualization of Protein Interaction Networks in vivo

Proteome-Wide Photo-Crosslinking Enables Residue-Level Visualization of Protein Interaction Networks in vivo

Two decades of Martini: Better beads, broader scope

Computing the Volume, Surface Area, Mean, and Gaussian Curvatures of Molecules and Their Derivatives

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