Coarse Grained Protein−Lipid Model with Application to Lipoprotein Particles

Shih, Amy Y.; Arkhipov, Anton; Freddolino, Peter L.; Schulten, Klaus

doi:10.1021/jp0550816

Cited by 252 publications

(308 citation statements)

References 60 publications

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“…The mass of each bead is the sum of its constituent atoms. Parameters for lipids and water were developed by Marrink et al (34), and parameters for proteins were developed by Shih et al (35). Protein parameters were initially developed on the basis of all-atom structures and simulations (35), and some were later refined further (36).…”

Section: Methodsmentioning

confidence: 99%

“…Protein parameters were initially developed on the basis of all-atom structures and simulations (35), and some were later refined further (36). The structure of the potential function is similar to the one of the all-atom CHARMM potential (35). After coarse-graining, the simulated system contained 9020 beads, over a factor of 10 less than the original 106 679 atoms.…”

Section: Methodsmentioning

confidence: 99%

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Structural Determinants of Lateral Gate Opening in the Protein Translocon

Gumbart

Schulten

2007

Biochemistry

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The heterotrimeric SecY/Sec61 complex is a protein-conducting channel that provides a passage for proteins across the membrane as well as a means to integrate nascent proteins into the membrane. While the first function is common among membrane protein channels and transporters, the latter is unique. Insertion of nascent membrane proteins, one transmembrane segment at a time, by SecY likely occurs through a lateral gate in the channel. Molecular dynamics simulations have been used to investigate the mechanism of gate opening. Opening and closing the gate under different conditions allowed us to identify structural elements that resist opening as well as those that aid closure. SecE, considered to act as a clamp keeping the lateral gate closed, was found to play no such role. Loosening of the plug by lateral gate opening, a potential step in channel gating, was also observed. The simulations revealed that lipids on time scales of up to 1 µs do not flood channels with an open lateral gate.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Structural Determinants of Lateral Gate Opening in the Protein Translocon

Gumbart

Schulten

2007

Biochemistry

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“…In one model (18), the SCs are used to calculate only the linear energy terms (i.e., virtual bonds and nonbonding interactions). Forces here are formulated in analogy to the full-atomic CHARMM force field; thus, the nonbonded interactions, virtual C␣-C␣ dihedrals, and bond angles are similar in character to CHARMM curvilinear terms.…”

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confidence: 99%

A force field for virtual atom molecular mechanics of proteins

Korkut¹,

Hendrickson

2009

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

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Activities of many biological macromolecules involve large conformational transitions for which crystallography can specify atomic details of alternative end states, but the course of transitions is often beyond the reach of computations based on full-atomic potential functions. We have developed a coarse-grained force field for molecular mechanics calculations based on the virtual interactions of C␣ atoms in protein molecules. This force field is parameterized based on the statistical distribution of the energy terms extracted from crystallographic data, and it is formulated to capture features dependent on secondary structure and on residue-specific contact information. The resulting force field is applied to energy minimization and normal mode analysis of several proteins. We find robust convergence in minimizations to low energies and energy gradients with low degrees of structural distortion, and atomic fluctuations calculated from the normal mode analyses correlate well with the experimental B-factors obtained from high-resolution crystal structures. These findings suggest that the virtual atom force field is a suitable tool for various molecular mechanics applications on large macromolecular systems undergoing large conformational changes.energy minimization ͉ normal modes ͉ transition pathways A ccurate understanding of the dynamic properties of proteins has been a major challenge in biophysics (1, 2). With advances in macromolecular crystallography, structural information has been obtained on very large complexes such as ribosome particles (3), chaperone complexes (4), virus particles (5), and RNA polymerases (6) as well as on thousands of individual proteins. In addition, snapshots of protein structures in different states of activity demonstrate the existence of very large conformational changes (7,8). Computational analysis of the dynamics of such systems is extremely difficult, if not impossible, when using full-atomic computational approaches, due not only to computational limitations but also to the complexity of the resulting information. Thus, coarse-grained approaches have gained importance for addressing large systems and large conformational changes (9-11).Coarse graining reduces computational complexity by greatly decreasing degrees of freedom of a molecular system with appropriate assumptions to achieve simplification without compromise of essential features (12). For reducing complexity in proteins, C␣-only models have been the most popular, but other coarse-graining approaches have also been taken, such as the inclusion of side-chain centroids (SCs) (13). An important aspect of coarse-grained analysis is the use of an appropriate pseudoforce field to model the forces and constraints exerted on the molecular system.The use of simple harmonic potentials to model the C␣-to-C␣ interactions in proteins as flexible springs has been most popular (14). Such simple harmonic potentials are very effective in defining the near-native-state fluctuations of proteins calculated by elastic network models...

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“…From here on these systems are denoted as toxin and villin. In the coarse-grained system, four heavy particles on average are represented as one sphere [28,29], which produces a total number of 7810 particles. The integrator step-size is set to 20 fs for optimal accuracy and 30 fs for optimal sampling.…”

Section: Resultsmentioning

confidence: 99%

Constant pressure hybrid Monte Carlo simulations in GROMACS

et al. 2014

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Adaptation and implementation of the Generalized Shadow Hybrid Monte Carlo (GSHMC) method for molecular simulation at constant pressure in the NPT ensemble are discussed. The resulting method, termed NPT-GSHMC, combines Andersen barostat with GSHMC to enable molecular simulations in the environment natural for biological applications, namely, at constant pressure and constant temperature. Generalized Hybrid Monte Carlo methods are designed to maintain constant temperature and volume and extending their functionality to preserving pressure is not trivial. The theoretical formulation of NPT-GSHMC was previously introduced. Our main contribution is the implementation of this methodology in the GROMACS molecular simulation package and the evaluation of properties of NPT-GSHMC, such as accuracy, performance, effectiveness for real physical systems in comparison with well-established molecular simulation techniques. Benchmarking tests are presented and the obtained preliminary results are promising. For the first time, the generalized hybrid Monte Carlo simulations at constant pressure are available within the popular open source molecular dynamics software package.

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Coarse Grained Protein−Lipid Model with Application to Lipoprotein Particles

Cited by 252 publications

References 60 publications

Structural Determinants of Lateral Gate Opening in the Protein Translocon

Structural Determinants of Lateral Gate Opening in the Protein Translocon

A force field for virtual atom molecular mechanics of proteins

Constant pressure hybrid Monte Carlo simulations in GROMACS

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