Molecular dynamics simulations of hydrophobic collapse of ubiquitin

Alonso, Darwin O. V.; Daggett, Valerie

doi:10.1002/pro.5560070404

Cited by 91 publications

(75 citation statements)

References 102 publications

(89 reference statements)

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“…This profile is similar to that obtained for the other proteins (data not shown). In other native-state simulations of ubiquitin, similar results have been reported (Alonso & Daggett 1998). In our case, the average C-a r.m.s.d.…”

Section: Resultssupporting

confidence: 91%

“…and R g for all four proteins are given in table 1. The R g values vary between 11 and 12 Å, typical for proteins of this size assuming a spherical conformation (Creighton 1984), and are in good agreement with the R g reported for other native-state simulations of ubiquitin (Alonso & Daggett 1998). These results demonstrate that no major structural change is taking place during the simulation, confirming that the protein remains within a native-state ensemble.…”

Section: Resultssupporting

confidence: 85%

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Native-state dynamics of the ubiquitin family: implications for function and evolution

Marianayagam

Jackson

2005

J. R. Soc. Interface.

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Protein dynamics are integral to protein function. In recent years, the use of computer simulation to understand the molecular motions of proteins has become widespread. However, there are few such studies which compare the dynamics of proteins that are structurally and functionally related. In this study, we present native-state molecular dynamic simulations of four proteins which possess a ubiquitin-like fold. Three of these proteins are thought to have evolved from a common ancestral ubiquitin-like protein and have similarities in their function. A fourth protein, which is structurally homologous but which appears to have a different function, is also studied. Local fluctuations in the native state simulations are analysed, and conserved motions of the C-a backbone atoms are identified in residues which are important for function. In addition, the global dynamics of the proteins are analysed using the essential-dynamics method. This analysis reveals a slightly higher degree of conservation in dynamics for the three proteins which are functionally related. Both the global and local analyses illustrate how nature has optimized and conserved protein motions for specific biological activity within the ubiquitin family.

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Section: Resultssupporting

confidence: 91%

Section: Resultssupporting

confidence: 85%

Native-state dynamics of the ubiquitin family: implications for function and evolution

Marianayagam

Jackson

2005

J. R. Soc. Interface.

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“…The stability of this N-terminal 1-37 fragment has been investigated by fragmentation studies, multidimensional NMR experiments, and MD simulation (41)(42)(43)(44)(45). MD simulations suggested a transition state with ␤-strands I, II, and V intact and an unfolding pathway involving strands III-V before unfolding of the hydrophobic core (45,46).…”

Section: Resultsmentioning

confidence: 99%

Transient 2D IR spectroscopy of ubiquitin unfolding dynamics

Chung

Ganim

Jones

et al. 2007

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

164

178

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Transient two-dimensional infrared (2D IR) spectroscopy is used as a probe of protein unfolding dynamics in a direct comparison of fast unfolding experiments with molecular dynamics simulations. In the experiments, the unfolding of ubiquitin is initiated by a laser temperature jump, and protein structural evolution from nanoseconds to milliseconds is probed using amide I 2D IR spectroscopy. The temperature jump prepares a subensemble near the unfolding transition state, leading to quasi-barrierless unfolding (the ''burst phase'') before the millisecond activated unfolding kinetics. The burst phase unfolding of ubiquitin is characterized by a loss of the coupling between vibrations of the ␤-sheet, a process that manifests itself in the 2D IR spectrum as a frequency blue-shift and intensity decrease of the diagonal and cross-peaks of the sheet's two IR active modes. As the sheet unfolds, increased fluctuations and solvent exposure of the ␤-sheet amide groups are also characterized by increases in homogeneous linewidth. Experimental spectra are compared with 2D IR spectra calculated from the time-evolving structures in a molecular dynamics simulation of ubiquitin unfolding. Unfolding is described as a sequential unfolding of strands in ubiquitin's ␤-sheet, using two collective coordinates of the sheet: (i) the native interstrand contacts between adjacent ␤-strands I and II and (ii) the remaining ␤-strand contacts within the sheet. The methods used illustrate the general principles by which 2D IR spectroscopy can be used for detailed dynamical comparisons of experiment and simulation. molecular dynamics ͉ protein folding ͉ temperature jump ͉ time-resolved spectroscopy F rom one perspective, protein folding is a chemical dynamics problem concerning description of the interplay of noncovalent interactions that involve the protein and surrounding solvent and exploration of the configurational space that leads to formation of the native structure. Although individually these interactions act on short time and distance scales, collectively they result in nanometer-scale conformational changes observed over time scales from picoseconds to seconds. The vast range of length and time scales, and the collective nature of folding coordinates, ensure that no single technique can time-resolve all relevant structural changes in solution (1-3). Most experimental methods favor either temporal or structural resolution and are limited to characterizing folding rates (kinetics) rather than mechanism (dynamics). From a computational approach, molecular dynamics (MD) simulations offer detailed dynamical information at atomic resolution for single molecules (4). Yet, simulation of folding is also challenged by the microsecond or longer time scales required, the need for extensive sampling of the ensemble, and only indirect experimental benchmarks. These challenges have spurred an interest in comparison between experiment and simulation that builds on their combined strengths to address mechanistic questions (5, 6).As an ultrafast vibrati...

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“…The N-terminal helix 1 rotated Ϸ30°while maintaining its helical structure. The C-terminal residue Phe 36 , which was found disordered in the NMR structure, also exhibited large scale movement. Phe 36 was initially in the solvent, as given by the NMR structure.…”

Section: Resultsmentioning

confidence: 99%

The early stage of folding of villin headpiece subdomain observed in a 200-nanosecond fully solvated molecular dynamics simulation

Duan

Wang

Kollman

1998

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

155

112

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A new approach in implementing classical molecular dynamics simulation for parallel computers has enabled a simulation to be carried out on a protein with explicit representation of water an order of magnitude longer than previously reported and will soon enable such simulations to be carried into the microsecond time range. We have used this approach to study the folding of the villin headpiece subdomain, a 36-residue small protein consisting of three helices, from an unfolded structure to a molten globule state, which has a number of features of the native structure. The time development of the solvation free energy, the radius of gyration, and the mainchain rms difference from the native NMR structure showed that the process can be seen as a 60-nsec ''burst'' phase followed by a slow ''conformational readjustment'' phase. We found that the burial of the hydrophobic surface dominated the early phase of the folding process and appeared to be the primary driving force of the reduction in the radius of gyration in that phase.Understanding the mechanism of protein folding has been a grand challenge in protein chemistry for a few decades. Important advances in this area can have a profound impact in many biologically relevant fields. A direct benefit from the understanding of the mechanism should be the ability to predict protein structures more accurately, which in turn should enable the pharmaceutical industry to improve drug discovery. The recent hypothesis of folding-related diseases is another example of the significance of folding (1, 2). Despite great progress made by a variety of experimental and theoretical approaches, it has been difficult to establish detailed descriptions of the folding process and mechanism at an atomic level.Computer simulation has been a powerful tool that can provide rich information at various levels of resolution. Simulation has been instrumental in understanding protein folding mechanisms. One such approach is lattice model simulations (3-5). These types of models use reduced representations by treating the residues as (one or two) linked beads. A more detailed approach is the atomic level model, either unitedatom or all-atom, which represents all or most of the atoms of the protein explicitly, with an implicit representation of the solvent (6, 7). Molecular dynamics (MD) simulations with full atomic representation of both protein and solvent possess a unique advantage to study protein folding because of their atomic level resolution and accuracy. This method with associated simulation parameters (i.e., the force field) derived from experiments and from gas-phase quantum mechanical calculations has been tested by using smaller molecular systems in many comparisons with experimental results.Because of the complexity of this approach, the large number of atoms, and the need to take time steps of 1 to 2 fsec, such simulations have to date been limited to a few nanoseconds; the longest single MD trajectories of proteins with explicit water have been Ͻ10 nsec (8). This has pre...

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Molecular dynamics simulations of hydrophobic collapse of ubiquitin

Cited by 91 publications

References 102 publications

Native-state dynamics of the ubiquitin family: implications for function and evolution

Native-state dynamics of the ubiquitin family: implications for function and evolution

Transient 2D IR spectroscopy of ubiquitin unfolding dynamics

The early stage of folding of villin headpiece subdomain observed in a 200-nanosecond fully solvated molecular dynamics simulation

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