Studies on protein folding, unfolding, and fluctuations by computer simulation. II. A. Three‐dimensional lattice model of lysozyme

Ueda, Yuzo; Taketomi, Hiroshi; Gō, Nobuhiro

doi:10.1002/bip.1978.360170612

Cited by 265 publications

(248 citation statements)

References 20 publications

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“…The desolvation potential, U(r), is designed as a function of the interacting distance, r, between residues involved in Go contacts (37), where rЈ is the minimum of the first potential well, r † is the maximum of the desolvation barrier, and rЉ is the minimum of the second potential well. The separation between rЈ and rЉ is the size of a single water and set to be 3.0 Å (ref.…”

Section: Appendix A: Design Of the Desolvation Modelmentioning

confidence: 99%

Protein folding mediated by solvation: Water expulsion and formation of the hydrophobic core occur after the structural collapse

Cheung

Garcı́a

Onuchic

2002

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

462

404

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The interplay between structure-search of the native structure and desolvation in protein folding has been explored using a minimalist model. These results support a folding mechanism where most of the structural formation of the protein is achieved before water is expelled from the hydrophobic core. This view integrates water expulsion effects into the funnel energy landscape theory of protein folding. Comparisons to experimental results are shown for the SH3 protein. After the folding transition, a near-native intermediate with partially solvated hydrophobic core is found. This transition is followed by a final step that cooperatively squeezes out water molecules from the partially hydrated protein core.T he energy landscape theory and the funnel concept combined with a new generation of experiments provide a new framework for understanding the protein folding problem. According to this ''new view,'' the folding landscape for proteins (at least for small fast folding proteins) resembles a partially rough funnel riddled with traps where the protein can transiently reside (1-8). Recent theoretical and experimental evidence fully support this picture and suggests that, because the energetic roughness of the landscape is sufficiently small (low level of energetic frustration), the global characteristics of the structural heterogeneity observed in the transition state ensemble for two-state fast folding proteins are most strongly determined by the native state topology. For this reason, theoretical energetically unfrustrated models have been shown to reproduce nearly all experimental results for the global geometrical features of the transition state ensemble of a large number of real proteins, which are two-state or three-state folders, on whose native structures they are based (9-24).Some concerns have been raised, however, about the applicability of these models. For example, solvent effects are incorporated implicitly into the energetic interactions between residues. Such implicit equilibrium models for solvation are unable to capture effects such as desolvation of the hydrophobic core; therefore, understanding the potential of mean force for the interaction between solutes in an aqueous solvent attracts the attention of many research groups (25-30). The potential of mean force (PMF) between two methane-like particles exhibit two minima-a contact minimum at the van der Waals distance between the particles and a solvent-separated minimum. The two minima are separated by a desolvation barrier with a width of approximately one water molecule diameter. Recently, Hillson et al. (31,32) advertised the importance of the desolvation effect by taking into account the process of expelling a water molecule in a pairwise interaction between hydrophobic particles. Assuming that the time scale for water penetration and escape are faster than the contact formation in proteins (33), the shape of this potential energy function implies that there are free-energy costs for protein (de)solvation (27). The time scale separation ass...

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Section: Appendix A: Design Of the Desolvation Modelmentioning

confidence: 99%

Protein folding mediated by solvation: Water expulsion and formation of the hydrophobic core occur after the structural collapse

Cheung

Garcı́a

Onuchic

2002

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

462

404

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“…41 Performing a survey of the energy landscape of the Gō-like model as for the BLN model above produced 805 transition states linking the 500 low-lying minima. The disconnectivity graph is shown in Figure 4.…”

Section: The Effects Of Frustrationmentioning

confidence: 99%

Energy landscape of a model protein

Miller¹,

Wales²

1999

The Journal of Chemical Physics

114

124

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The potential energy surface of an off-lattice model protein is characterized in detail by constructing a disconnectivity graph and by examining the organisation of pathways on the surface. The results clearly reveal the frustration exhibited by this system and explain why it does not fold efficiently to the global potential energy minimum. In contrast, when the frustration is removed by constructing a 'Gō-type' model, the resulting graph exhibits the characteristics expected for a folding funnel.

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“…Because the energetic roughness is minimal, the structural heterogeneity observed in the transitionstate ensemble (TSE) is strongly influenced by the topological effects, which, to a large extent, may be inferred from the native structure (11)(12)(13)(14)(15)(16). This explains why simple energetically unfrustrated (Go -like) models (17) reproduce nearly all experimental results for the global geometrical features of the TSE and͞or intermediates of a large number of real proteins, which are two-or three-state folders (13). These models have been recently generalized to include the ability to capture effects such as the desolvation of the hydrophobic core (14).…”

mentioning

confidence: 99%

Solvation in protein folding analysis: Combination of theoretical and experimental approaches

Fernández-Escamilla

Cheung

Vega

et al. 2004

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

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An effort to combine theoretical analyses and protein engineering methods has been made to probe the folding mechanism of SH3 by using Energy Landscape Theory and a -value analysis. Particular emphasis was given to core residues and the effect of desolvation during the folding event by replacing the core valines with isosteric threonines. These mutations have the advantage of keeping the core structurally invariant while affecting core stability relative to the unfolded state. Although the valines that form the core appear spatially invariant, the folding kinetics of their threonine mutants varies, indicating their different extent of solvation in the transition-state ensemble. Theoretical studies predicted the distribution of folding kinetics of threonine mutants without previous knowledge of the measured rates. This initial success encourages further investigations of the molecular details behind these macroscopic phenomena and of the role of solvation in the folding mechanism.A large body of recent data suggests that proteins, especially small fast-folding (submillisecond) proteins (1-3), have sequences with a level of energetic frustration sufficiently reduced that their overall energy landscape (4-8) resembles a moderately rough funnel (9). The landscape roughness corresponds to local free energy minima arising from geometric (topological) and energetic traps (10). Geometric or topological traps are associated with chain connectivity and the shape of the native fold and occur when correct contacts form prematurely (10). Because the energetic roughness is minimal, the structural heterogeneity observed in the transitionstate ensemble (TSE) is strongly influenced by the topological effects, which, to a large extent, may be inferred from the native structure (11-16). This explains why simple energetically unfrustrated (Go -like) models (17) reproduce nearly all experimental results for the global geometrical features of the TSE and͞or intermediates of a large number of real proteins, which are two-or three-state folders (13). These models have been recently generalized to include the ability to capture effects such as the desolvation of the hydrophobic core (14).Using this theoretical framework, the funnel landscape coupled with microscopic desolvation can be pictured by using two ordering parameters: Q, a fraction of the total native contact formation, and pseudo Q, a fraction of the total single-water separated native contact formation (14). The latter is a direct consequence of using a pairwise potential with a characteristic desolvation barrier, which accounts for entropy costs to expel a single water molecule between two interacting apolar groups before a full contact can be made (14,(18)(19)(20). Although no explicit water molecule has been included in the simulations, the emergence of this desolvation barrier emulates the granular properties of solvents. By using this model, we have recently predicted that the folding of SH3 is controlled by a structural-search collapse followed by desolvation of the hyd...

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Studies on protein folding, unfolding, and fluctuations by computer simulation. II. A. Three‐dimensional lattice model of lysozyme

Cited by 265 publications

References 20 publications

Protein folding mediated by solvation: Water expulsion and formation of the hydrophobic core occur after the structural collapse

Protein folding mediated by solvation: Water expulsion and formation of the hydrophobic core occur after the structural collapse

Energy landscape of a model protein

Solvation in protein folding analysis: Combination of theoretical and experimental approaches

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