Simulations of the role of water in the protein-folding mechanism

Abstract

There are many unresolved questions regarding the role of water in protein folding. Does water merely induce hydrophobic forces, or does the discrete nature of water play a structural role in folding? Are the nonadditive aspects of water important in determining the folding mechanism? To help to address these questions, we have performed simulations of the folding of a model protein (BBA5) in explicit solvent. Starting 10,000 independent trajectories from a fully unfolded conformation, we have observed numerous folding events, making this work a comprehensive study of the kinetics of protein folding starting from the unfolded state and reaching the folded state and with an explicit solvation model and experimentally validated rates. Indeed, both the raw TIP3P folding rate (4.5 ؎ 2.5 s) and the diffusion-constant corrected rate (7.5 ؎ 4.2 s) are in strong agreement with the experimentally observed rate of 7.5 ؎ 3.5 s. To address the role of water in folding, the mechanism is compared with that predicted from implicit solvation simulations. An examination of solvent density near hydrophobic groups during folding suggests that in the case of BBA5, there are water-induced effects not captured by implicit solvation models, including signs of a ''concurrent mechanism'' of core collapse and desolvation.explicit solvation model ͉ distributed computing ͉ molecular dynamics W hen considering the nature of the protein folding mechanism, because of the dominance of the hydrophobic effect, one must consider the role of water. Water can be examined explicitly by studying discrete water molecules. However, it is common to consider the role of water implicitly in terms of its bulk dielectric property and interaction with hydrophobic groups of the protein. Implicit solvation methods have been widely adopted in the computational study of folding dynamics, where such dielectric and hydrophobic properties are accounted for with continuum models. In addition, it is interesting to consider that experiments assessing the folding mechanism (e.g., ⌽-value analysis) are typically interpreted in terms of an implicit role of water. For example, the stabilization or destabilization of protein-protein interactions is accounted for based on physical forces mediated by water, rather than an accounting of the role of specific, explicit water molecules.However, there are important properties of water which are not considered in typical implicit solvation models. In particular, the nonadditive nature of hydrophobicity leads to the so-called ''drying effect,'' in which a layer of vacuum surrounds hydrophobic surfaces and makes hydrophobic collapse cooperative (1). In addition, continuum models of water do not account for the discrete nature of water molecules, which may lead to differences in protein folding dynamics, such as a cooperative expulsion of water upon folding (2). It is also known that structured water plays a role in the folded state of many proteins (3). Accordingly, one can imagine that water may play a ''structural role'' in some o...

Molecular dynamics simulation exploration of unfolding and refolding of a ten-amino acid miniprotein

“…The phenomenon is very different from what happens in other peptides, where force is always positive. As the C-terminus detaches from the N-terminus, stable hydrogen bonds break soon by continuous attacks from water molecules (Rhee et al 2004;Li et al 2010;Shelimov et al 1997).…”

Reconstruction of the src-SH3 Protein Domain Transition State Ensemble using Multiscale Molecular Dynamics Simulations

“…In a similar vein, recent simulations by Pande on the BBA5 mini-protein indicate that P fold values computed in both implicit and explicit solvent are in qualitative agreement. 31 Use of a fully atomic potential can enrich the putative TSE and, when combined with P fold calculations using a coarsegrained model, can yield atomically detailed insight into at least a subset of the entire TSE.…”

“…In recent simulations, Pande and co-workers implemented a 5 ns cutoff for P fold calculations of the microsecond folding miniprotein BBA5, which would translate to simulations of the order of microseconds for a millisecond folder. 31 In addition, a reliable characterization of the transition state using the P fold criterion would require multiple folding runs from each of the multiple putative transition state structures. Hence, rather than using fully-atomic, solvated simulations to determine P fold , we employ the discrete molecular dynamics simulations, 32,33 using a Go interaction model to calculate the P fold values for the selected putative TSE conformations.…”

Convergence of folding free energy landscapes via application of enhanced sampling methods in a distributed computing environment

“…1,2 Recently, it has been shown that a large ensemble of individual MD trajectories generated by a distributed computing network makes it possible to study the folding of some miniproteins in explicit solvent. [3][4][5][6][7][8] Unfortunately, due to the local trapping problem, it is still difficult to satisfactorily sample the entire configuration space of a biomolecule in explicit solvent even with a distributed computing effort. Tempering methods such as simulated tempering 9,10 ͑ST͒ and parallel tempering ͓or replica exchange method ͑REM͔͒ [11][12][13][14] were developed to overcome this kinetic trapping problem by inducing a random walk in temperature space.…”