Molecular dynamics simulations of large macromolecular complexes

Perilla, Juan R.; Goh, Boon Chong; Cassidy, C. Keith; Liu, Bo; Bernardi, Rafael C.; Rudack, Till; Yu, Hang; Wu, Zhe; Schulten, Klaus

doi:10.1016/j.sbi.2015.03.007

Cited by 387 publications

(311 citation statements)

References 105 publications

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“…To build an accurate atomic model of the human 26S proteasome, we followed the strategy established for large macromolecular complexes (27,28). We first built comparative models of the human 26S proteasome subunits, extended template-free segments by de novo modeling, and superposed these human subunit models onto their respective yeast homologs.…”

Section: Resultsmentioning

confidence: 99%

Structure of the human 26S proteasome at a resolution of 3.9 Å

Schweitzer

Aufderheide

Rudack

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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187

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Protein degradation in eukaryotic cells is performed by the UbiquitinProteasome System (UPS). The 26S proteasome holocomplex consists of a core particle (CP) that proteolytically degrades polyubiquitylated proteins, and a regulatory particle (RP) containing the AAA-ATPase module. This module controls access to the proteolytic chamber inside the CP and is surrounded by non-ATPase subunits (Rpns) that recognize substrates and deubiquitylate them before unfolding and degradation. The architecture of the 26S holocomplex is highly conserved between yeast and humans. The structure of the human 26S holocomplex described here reveals previously unidentified features of the AAA-ATPase heterohexamer. One subunit, Rpt6, has ADP bound, whereas the other five have ATP in their binding pockets. Rpt6 is structurally distinct from the other five Rpt subunits, most notably in its pore loop region. For Rpns, the map reveals two main, previously undetected, features: the C terminus of Rpn3 protrudes into the mouth of the ATPase ring; and Rpn1 and Rpn2, the largest proteasome subunits, are linked by an extended connection. The structural features of the 26S proteasome observed in this study are likely to be important for coordinating the proteasomal subunits during substrate processing.proteostasis | cryo-electron microscopy | AAA-ATPase | integrative modeling T he 26S proteasome is an ATP-dependent multisubunit protease degrading polyubiquitylated proteins (1, 2). It operates at the executive end of the Ubiquitin-Proteasome System (UPS) and has a key role in cellular proteostasis. The 26S proteasome selectively removes misfolded proteins or proteins no longer needed and it is critically involved in numerous cellular processes such as protein quality control, regulation of metabolism, cell cycle control, or antigen presentation. Malfunctions of the UPS are associated with various pathologies, including neurodegenerative diseases and cancer. Therefore, the proteasome is an important pharmaceutical target, and a high-resolution structure is a prerequisite for structure-based drug design (3).The 26S proteasome comprises the 20S cylindrical core particle (CP), where proteolysis takes place, and 19S regulatory particles (RPs). In cellular environments, 26S holocomplexes with either one or two RPs bound to the ends of the cylindershaped CP coexist (4). The role of the RPs is to recruit ubiquitylated substrates, to cleave off their polyubiquitin tags, and to unfold and translocate them into the CP for degradation into short peptides. Whereas X-ray crystallography has revealed the atomic structures first of archaeal 20S proteasome (5) and subsequently of the yeast (6) and mammalian proteasome (7), only lower-resolution structures were available for the 26S holocomplex. Given the compositional and conformational heterogeneity of the RP, single-particle cryo-electron microscopy (cryo-EM) has been the most successful approach to determining the structure of the 26S holocomplex (8). At this point, the most detailed insights have been obtained ...

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Section: Resultsmentioning

confidence: 99%

Structure of the human 26S proteasome at a resolution of 3.9 Å

Schweitzer

Aufderheide

Rudack

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

187

220

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“…Therefore, in order to simulate larger systems, hybrid approaches [12,[57][58][59] must be followed. In such a method, a small region of interest is simulated with ab initio molecular dynamics, while the rest of the molecular system is approximated with molecular mechanics:…”

Section: Hybrid Quantum Mechanics-molecular Dynamics Methodsmentioning

confidence: 99%

Computational Methods for Ab Initio Molecular Dynamics

Paquet

Viktor

2018

Advances in Chemistry

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Ab initio molecular dynamics is an irreplaceable technique for the realistic simulation of complex molecular systems and processes from first principles. This paper proposes a comprehensive and self-contained review of ab initio molecular dynamics from a computational perspective and from first principles. Quantum mechanics is presented from a molecular dynamics perspective. Various approximations and formulations are proposed, including the Ehrenfest, Born-Oppenheimer, and Hartree-Fock molecular dynamics. Subsequently, the Kohn-Sham formulation of molecular dynamics is introduced as well as the afferent concept of density functional. As a result, Car-Parrinello molecular dynamics is discussed, together with its extension to isothermal and isobaric processes. Car-Parrinello molecular dynamics is then reformulated in terms of path integrals. Finally, some implementation issues are analysed, namely, the pseudopotential, the orbital functional basis, and hybrid molecular dynamics.

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“…Especially under crowding conditions, membrane dynamics slow down, and sampling of the motions of individual membrane proteins -let alone of protein complexes -becomes a serious issue (Goose and Sansom, 2013;Javanainen et al, 2013). The use of massively parallel computer resources or dedicated hardware can extend the range of applicability of all-atom models to a certain extent (Perilla et al, 2015). For instance, short all-atom simulations of an entire organelle (Chandler et al, 2014) or all-atom simulations totalling over 100 μs of a G-protein-coupled receptor (GPCR) embedded in a small lipid membrane patch (Dror et al, 2011) have in fact been reported, but these are associated with a computational cost that is not available to everyone.…”

Section: Atomic Resolutionmentioning

confidence: 99%

Computational ‘microscopy’ of cellular membranes

Ingólfsson

Arnarez²,

Periole³

et al. 2016

Journal of Cell Science

136

120

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Computational 'microscopy' refers to the use of computational resources to simulate the dynamics of a molecular system. Tuned to cell membranes, this computational 'microscopy' technique is able to capture the interplay between lipids and proteins at a spatiotemporal resolution that is unmatched by other methods. Recent advances allow us to zoom out from individual atoms and molecules to supramolecular complexes and subcellular compartments that contain tens of millions of particles, and to capture the complexity of the crowded environment of real cell membranes. This Commentary gives an overview of the main concepts of computational 'microscopy' and describes the state-of-the-art methods used to model cell membrane processes. We illustrate the power of computational modelling approaches by providing a few in-depth examples of largescale simulations that move up from molecular descriptions into the subcellular arena. We end with an outlook towards modelling a complete cell in silico.

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Molecular dynamics simulations of large macromolecular complexes

Cited by 387 publications

References 105 publications

Structure of the human 26S proteasome at a resolution of 3.9 Å

Structure of the human 26S proteasome at a resolution of 3.9 Å

Computational Methods for Ab Initio Molecular Dynamics

Computational ‘microscopy’ of cellular membranes

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