Role of Water Mediated Interactions in Protein−Protein Recognition Landscapes

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Natural protein domains must be sufficiently stable to fold but often need to be locally unstable to function. Overall, strong energetic conflicts are minimized in native states satisfying the principle of minimal frustration. Local violations of this principle open up possibilities to form the complex multifunnel energy landscapes needed for large-scale conformational changes. We survey the local frustration patterns of allosteric domains and show that the regions that reconfigure are often enriched in patches of highly frustrated interactions, consistent both with the idea that these locally frustrated regions may act as specific hinges or that proteins may "crack" in these locations. On the other hand, the symmetry of multimeric protein assemblies allows near degeneracy by reconfiguring while maintaining minimally frustrated interactions. We also anecdotally examine some specific examples of complex conformational changes and speculate on the role of frustration in the kinetics of allosteric change.minimal frustration principle | protein folding | protein function A llostery and large-scale conformational changes are widespread in molecular biology but historically have been considered to be exceptional and somewhat mysterious. In fact, cryobiochemical (1) and single molecule (2) experiments show that the underlying energy landscapes of all biomolecules are generally quite complex (3). These findings surprised many because there has been so much success in modeling even large pieces of biological machinery as simple chemical entities obeying elementary laws of equilibrium and kinetics (4). The mystery of allostery was thus a first hint of landscape complexity (5). In contrast to experimentalists, who were surprised by emergent complexity, theorists are more surprised by the seeming simplicity of the free energy landscape of proteins at physiological temperatures. Theorists expect that the apparent randomness of a protein sequence will result in many competing forces between residues, and thus structurally disparate states should be at least transiently populated (6). Indeed statistical mechanical theory suggests completely random heteropolymers have rugged landscapes, like glasses, which provide paradigms of complex kinetics (7-9). The resolution of this dialectic lies in evolution: Proteins emerge from selected sequences that give rise to organized energy landscapes. Most of this organization encodes the ability of the molecule to spontaneously find a fairly specific (although decidedly not unique) configuration, the so-called folded or average native structure. By having specific structures, proteins become limited in their range of interaction partners thus allowing complex networks of biological interactions to be built up. Overall, the energy landscapes of proteins resemble a rough funnel leading toward the native state (10, 11). This funnel structure is only possible for those selected sequences that are chosen so that energetic conflicts are for the most part avoided and the native structure is more st...

Section: Resultsmentioning

confidence: 99%

On the role of frustration in the energy landscapes of allosteric proteins

Ferreiro

Hegler

Komives³

et al. 2011

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“…In a monomeric protein the alternate configurations caused by locally frustrating an otherwise largely unfrustrated structure could provide specific control of the thermal motions, so the protein can function much like a macroscopic machine having only a few moving parts. Alternatively, a site frustrated in a monomeric protein may become less frustrated in the final larger assembly containing that protein, thus guiding specific association (9,10). Thermodynamic folding studies of enzymes also show that catalytic sites exhibit signs of frustration (31,32).…”

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confidence: 99%

Localizing frustration in native proteins and protein assemblies

Ferreiro

Hegler

Komives

et al. 2007

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322

441

We propose a method of quantifying the degree of frustration manifested by spatially local interactions in protein biomolecules. This method of localization smoothly generalizes the global criterion for an energy landscape to be funneled to the native state, which is in keeping with the principle of minimal frustration. A survey of the structural database shows that natural proteins are multiply connected by a web of local interactions that are individually minimally frustrated. In contrast, highly frustrated interactions are found clustered on the surface, often near binding sites. These binding sites become less frustrated upon complex formation.protein folding ͉ protein function ͉ energy landscape

“…Hydrophobicity plays an important role in such diverse systems as the self-assembly of amphiphiles (13,14), the gating of ion channels (15), and the formation of stable protein structures (16)(17)(18)(19). Here we focus on the effect of hydrophobic carbonaceous groups (−CH n − , n ¼ 1, 2, 3) on both hydrophobic and hydrophilic amino acid residues.…”

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confidence: 99%

Water’s role in the force-induced unfolding of ubiquitin

Fernández

Berne

2010

In atomic force spectroscopic studies of the elastomeric protein ubiquitin, the β-strands 1-5 serve as the force clamp. Simulations show how the rupture force in the force-induced unfolding depends on the kinetics of water molecule insertion into positions where they can eventually form hydrogen bonding bridges with the backbone hydrogen bonds in the force-clamp region. The intrusion of water into this region is slowed down by the hydrophobic shielding effect of carbonaceous groups on the surface residues of β-strands 1-5, which thereby regulates water insertion prior to hydrogen bond breakage. The experiments show that the unfolding of the mechanically stressed protein is nonexponential due to static disorder. Our simulations show that different numbers and/ or locations of bridging water molecules give rise to a long-lived distribution of transition states and static disorder. We find that slowing down the translational (not rotational) motions of the water molecules by increasing the mass of their oxygen atoms, which leaves the force field and thereby the equilibrium structure of the solvent unchanged, increases the average rupture force; however, the early stages of the force versus time behavior are very similar for our "normal" and fictitious "heavy" water models. Finally, we construct six mutant systems to regulate the hydrophobic shielding effect of the surface residues in the force-clamp region. The mutations in the two termini of β-sheets 1-5 are found to determine a preference for different unfolding pathways and change mutant's average rupture force. T here is a growing interest in the kinetic mechanisms by which elastomeric proteins unfold under force, as these proteins are involved in a wide variety of biological processes. Most elastomeric proteins (e.g., ubiquitin, I27, and fnIII) (1-3) share the common structural feature of having β-rich structures, populated by parallel β-strands. In atomic force spectroscopic studies of the elastomeric protein ubiquitin, the β-strands 1-5 serve as the force clamp under shear loading. Steered molecular dynamics (SMD) simulations (2, 4) showed that the shear loading force needs to break all four backbone hydrogen bonds (bbHBs) between the parallel β-strands 1-5 of ubiquitin in order to trigger protein unfolding (1,(5)(6)(7)(8). In SMD simulations of I27, Lu and Schulten observed that in the early stages of the pulling process individual bbHBs occasionally break and quickly reform, due to thermal fluctuations. During these fluctuations water molecules interact with the groups of broken bbHBs, but after several picoseconds these water molecules leave the region and the bbHBs reform (9). The bbHBs in the clamp region were thought to break simultaneously right before the sheet ruptures (2, 9, 10). In our SMD studies we observe that in ubiquitin under the pulling forces the four bbHBs in the β-strands 1-5 break sequentially from either the N or C termini, accompanied by the insertion of water molecules into the broken bbHBs to form stable bridging hydrogen bonds with...