Contribution of Hydration to Protein Folding Thermodynamics

Privalov, Peter L.; Makhatadze, George I.

doi:10.1006/jmbi.1993.1417

Cited by 404 publications

(332 citation statements)

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“…Relying on small molecule thermodynamic transfer data [59][60] , this corresponds to the release of ~ 200 water molecules, which for a protein with a binding cavity of ~1000 Å 3 , seems reasonable. 61 Tochtrop et al 9 has also performed ITC experiments to characterize the temperature dependence of the binding interaction for the human I-BABP:GCA complex.…”

Section: Discussionmentioning

confidence: 99%

Temperature Dependence of Backbone Dynamics in Human Ileal Bile Acid-Binding Protein: Implications for the Mechanism of Ligand Binding

2014

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Human ileal bile acid-binding protein (I-BABP), a member of the family of intracellular lipid binding proteins plays a key role in the cellular trafficking and metabolic regulation of bile salts.The protein has two internal and according to a recent study an additional superficial binding site and binds di-and trihydroxy bile salts with positive cooperativity and a high degree of siteselectivity. Previously, in the apo form, we have identified an extensive network of conformational fluctuations on the ms time scale, which cease upon ligation. Additionally, ligand binding at room temperature was found to be accompanied by a slight rigidification of psns backbone flexibility. In the current study, temperature-dependent 15 N NMR spin relaxation measurements were used to gain more insight into the role of dynamics in human I-BABP -bile salt recognition. According to our analysis, residues sensing a conformational exchange in the apo state can be grouped into two clusters with slightly different exchange rates. The entropyenthalpy compensation observed for both clusters suggests a disorder-order transition between a ground and a sparsely populated higher energy state in the absence of ligands. Analysis of the faster, ps-ns motion of 15 N-1 H bond vectors indicates an unusual nonlinear temperaturedependence for both ligation states. Intriguingly, while bile salt binding results in a more uniform response to temperature change throughout the protein, the temperature derivative of the generalized order parameter shows different responses to temperature increase for the two forms of the protein in the investigated temperature range. Analysis of both slow and fast motions in human I-BABP indicates largely different energy landscapes for the apo and holo states suggesting that optimization of binding interactions might be achieved by altering the dynamic behavior of specific segments in the protein. 4Human ileal bile acid binding protein (I-BABP), expressed in the absorptive enterocytes of the distal small intestine has a key role in the enterohepatic circulation of bile salts. 1 In addition to aiding the absorption of lipidlike compounds in the human body 2 , bile salts (Figure 1) are also known as signal molecules, which play important roles in the regulation of metabolic processes.In particular, by binding to the nuclear farnesoid X receptor α (FXR) 3 they provide a negative feedback mechanism for their own synthesis thereby contributing to the maintenance of wholebody cholesterol homeostasis. In addition, by the activation of various mitogen-activated protein kinase pathways and the interaction with the G-protein-coupled receptor TGR5, they participate in the regulation of triglyceride, energy, and glucose metabolism. 4

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Section: Discussionmentioning

confidence: 99%

Temperature Dependence of Backbone Dynamics in Human Ileal Bile Acid-Binding Protein: Implications for the Mechanism of Ligand Binding

2014

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“…Extension of such a collapsed state can firstly account for significant length increases [19] by linear extension of the polypeptide chain. Secondly, the resulting exposure of hydrophobic residues to cytosolic water is an energy-consuming step [20,21]. Exposure of hydrophobic residues would create a significant entropic driving force [20,21] of the 'unfolded', extended form of the PEVKrich segment to provide a strong spring that would recoil when external strain is released.…”

Section: Discussionmentioning

confidence: 99%

“…Secondly, the resulting exposure of hydrophobic residues to cytosolic water is an energy-consuming step [20,21]. Exposure of hydrophobic residues would create a significant entropic driving force [20,21] of the 'unfolded', extended form of the PEVKrich segment to provide a strong spring that would recoil when external strain is released. Indeed, previous biomechanical studies have shown that passive tension of skeletal muscle shows a temperature-dependent behaviour expected for an entropic mechanism involving the exposure of hydrophobic side chains [15].…”

Section: Discussionmentioning

confidence: 99%

A molecular map of titin/connectin elasticity reveals two different mechanisms acting in series

1996

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In the I-band of skeletal muscle sarcomeres, the elastic region of titin consists of immunoglobulin (Ig) domains, and non-modular regions rich in proline, hydrophobic, and charged residues (PEVK). Using immunoelectron microscopy with sequence-assigned monoclonal antibodies, we demonstrate that extension of the Ig regions in M. psoas occurs largely at sarcomere lengths between 2 and 2.8 pm, decreasing in slope towards higher lengths. The Ig domains do not unfold. Above 2.6 pm, length changes are increasingly due to the PEVK-rich regions. We therefore propose that rubber-like properties of the PEVK-rich regions are mainly contributing to skeletal titin elasticity.

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“…14 That entropy convergence coincides with the observed temperature convergence of the entropy of protein unfolding and thus provides a thermodynamic foundation for the hydrophobic-core model of protein folding. 6,7,11,12,16,17,18 In addition, we will suggest a molecular mechanism for pressure denaturation of proteins 19,20,21,22,23,24,25,26 and discuss its consequences on folding kinetics and the characteristics of the ensemble of unfolded protein structures. 15 Our explanation of pressure denaturation invokes experimental observations regarding the differences in the structures of heat and pressure-denatured proteins, the latter being more compact.…”

Section: Introductionmentioning

confidence: 99%

Hydrophobic Effects on a Molecular Scale

et al. 1998

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A theoretical approach is developed to quantify hydrophobic hydration and interactions on a molecular scale, with the goal of insight into the molecular origins of hydrophobic effects. The model is based on the fundamental relation between the probability for cavity formation in bulk water resulting from molecular-scale density fluctuations, and the hydration free energy of the simplest hydrophobic solutes, hard particles. This probability is estimated using an information theory (IT) approach, incorporating experimentally available properties of bulk water -the density and radial distribution function. The IT approach reproduces the simplest hydrophobic effects: hydration of spherical nonpolar solutes, the potential of mean force (PMF) between methane molecules, and solvent contributions to the torsional equilibrium of butane. Applications of this approach to study temperature and pressure effects provide new insights into the thermodynamics and kinetics of protein folding. The IT model relates the hydrophobic-entropy convergence observed in protein unfolding experiments to the macroscopic isothermal compressibility of water. A novel explanation for pressure denaturation of proteins follows from an analysis of the pressure stability of hydrophobic aggregates, suggesting that water penetrates the hydrophobic core of proteins at high pressures. This resolves a long-standing puzzle, whether pressure denaturation contradicts the hydrophobic-core model of protein stability. Finally, issues of "dewetting" of molecularly large nonpolar solutes are discussed in the context of a recently developed perturbation theory approach.

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Contribution of Hydration to Protein Folding Thermodynamics

Cited by 404 publications

References 0 publications

Temperature Dependence of Backbone Dynamics in Human Ileal Bile Acid-Binding Protein: Implications for the Mechanism of Ligand Binding

Temperature Dependence of Backbone Dynamics in Human Ileal Bile Acid-Binding Protein: Implications for the Mechanism of Ligand Binding

A molecular map of titin/connectin elasticity reveals two different mechanisms acting in series

Hydrophobic Effects on a Molecular Scale

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