Thermodynamics of the temperature‐induced unfolding of globular proteins

Хечинашвили, Н. Н.; Janin, Joël; Rodier, Françis

doi:10.1002/pro.5560040707

Cited by 52 publications

(28 citation statements)

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“…The polar contribution coefficient, -0.26 cal/mol/A', is based on the thermodynamics of aqueous dissolution of solid cyclic dipeptides (Mur-phy et al, 1990). The analysis of the specific heat capacity increments upon protein unfolding yields similar contribution coefficients (Ooi et al, 1987;Spolar et al, 1992;Khechinashvili et al, 1995;Makhatadze & Privalov, 1995).…”

Section: Calorimet? Of Protein Unfoldingmentioning

confidence: 92%

“…Because protein folding and association are governed by the same physical forces, under appropriate conditions, Equation 1 should also apply to folding (Khechinashvili et al, 1995). As we will describe, the folding free energy has been expressed as a linear combination of the changes in apolar and polar solvent-accessible surface areas, with coefficients determined from calorimetric data.…”

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confidence: 99%

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Empirical free energy calculation: Comparison to calorimetric data

Weng¹,

DeLisi²,

Vajda³

1997

Protein Science

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An effective free energy potential, developed originally for binding free energy calculation, is compared to calorimetric data on protein unfolding, described by a linear combination of changes in polar and nonpolar surface areas. The potential consists of a molecular mechanics energy term calculated for a reference medium (vapor or nonpolar liquid), and empirical terms representing solvation and entropic effects. It is shown that, under suitable conditions, the free energy function agrees well with the calorimetric expression. An additional result of the comparison is an independent estimate of the side-chain entropy loss, which is shown to agree with a structure-based entropy scale. These findings confirm that simple functions can be used to estimate the free energy change in complex systems, and that a binding free energy evaluation model can describe the thermodynamics of protein unfolding correctly. Furthermore, it is shown that folding and binding leave the sum of solute-solute and solute-solvent van der Waals interactions nearly invariant and, due to this invariance, it may be advantageous to use a nonpolar liquid rather than vacuum as the reference medium.Keywords: binding free energy; free energy calculation; heat capacity; protein unfolding Calculating the free energy change in protein folding and association is a classical problem in biophysical chemistry. In principle, free energy differences can be obtained by molecular dynamics and Monte Carlo simulations that allow for similar molecules to be interconverted, and the relative free energies determined by perturbation or integration techniques (Mezei & Beveridge, 1986; Reynolds et al., 1992). However, simulation methods are far too expensive computationally for free energy calculation in conformational search, docking, and design (Wilson et al., 1991). The simplest remedy is to neglect solvation and entropic contributions in applications, but it is well known that energy-type target functions are frequently unable to distinguish between correct and incorrect proteins folds (Novotny et al., 1988), or correct and incorrect docked conformations (Shoichet & Kuntz, 1991 becoming the standard in computer-aided molecular design (Ajay & Murcko, 1995).We have developed a relatively complete empirical free energy function, and evaluated it against a range of structural and thermodynamic data (Vajda et al., Gulukota et al., 1996;King et al., 1996; Weng et ai., 1996). The free energy change, AG = G2 -G I , between two states is calculated according to the expression:where AE, Act,, and AS, represent the energy change, the desolvation free energy, and the change in conformational entropy, respectively. The last term, AC,,t/lrrr includes all other free energy changes associated with translational, rotational, vibrational, cratic, and protonation/deprotonation effects (Novotny et al., 1989; Vajda et al., 1994).The function has been developed originally for calculating receptor-ligand binding free energies, and we used a number of simplifying assumptions t...

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Section: Calorimet? Of Protein Unfoldingmentioning

confidence: 92%

mentioning

confidence: 99%

Empirical free energy calculation: Comparison to calorimetric data

Weng¹,

DeLisi²,

Vajda³

1997

Protein Science

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“…The unfolded state of the protein was taken to be an extended β‐structure, simulated with the Biopolymer module of INSIGHTII software on an INDIGO O 2 Workstation. We used formulas deduced elsewhere [29–31] to estimate the Δ C p value from changes in solvent‐accessible areas (ΔASA).…”

Section: Methodsmentioning

confidence: 99%

AS‐48: a circular protein with an extremely stable globular structure

et al. 2001

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The unfolding thermodynamics of the circular enterocin protein AS-48, produced by Enterococcus faecalis, has been characterized by differential scanning calorimetry. The native structure of the 70-residue protein is extremely thermally stable. Thus, at pH 2.5 and low ionic strength thermal denaturation occurs under equilibrium at 102³C, while the unfolded state irreversibly aggregates at neutral and alkaline pH. Calorimetric data analysis shows that the specific enthalpy change upon unfolding is unusually small and the heat capacity change is quite normal for a protein of this size, whereas the Gibbs energy change at 25³C is relatively high. At least part of this high stability might be put down to entropic constraints induced by the circular organization of the polypeptide chain. ß

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“…Temperature provides conformational flexibility to proteins for enzymatic activities by increasing their conformational fluctuations (24). Nevertheless, sufficiently high temperature may also distort protein structure and cause unfolding or denaturation (25)(26)(27). Another thermodynamic parameter, pressure, also plays an important role in protein structure and dynamics (28)(29)(30)(31)(32)(33).…”

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confidence: 99%

Effects of pressure on the dynamics of an oligomeric protein from deep-sea hyperthermophile

Shrestha

Bhowmik

Copley

et al. 2015

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

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Inorganic pyrophosphatase (IPPase) from Thermococcus thioreducens is a large oligomeric protein derived from a hyperthermophilic microorganism that is found near hydrothermal vents deep under the sea, where the pressure is up to 100 MPa (1 kbar). It has attracted great interest in biophysical research because of its high activity under extreme conditions in the seabed. In this study, we use the quasielastic neutron scattering (QENS) technique to investigate the effects of pressure on the conformational flexibility and relaxation dynamics of IPPase over a wide temperature range. The β-relaxation dynamics of proteins was studied in the time ranges from 2 to 25 ps, and from 100 ps to 2 ns, using two spectrometers. Our results indicate that, under a pressure of 100 MPa, close to that of the native environment deep under the sea, IPPase displays much faster relaxation dynamics than a mesophilic model protein, hen egg white lysozyme (HEWL), at all measured temperatures, opposite to what we observed previously under ambient pressure. This contradictory observation provides evidence that the protein energy landscape is distorted by high pressure, which is significantly different for hyperthermophilic (IPPase) and mesophilic (HEWL) proteins. We further derive from our observations a schematic denaturation phase diagram together with energy landscapes for the two very different proteins, which can be used as a general picture to understand the dynamical properties of thermophilic proteins under pressure.protein dynamics | energy landscape | denaturation phase diagram | quasielastic neutron scattering | mode coupling theory T he biological functions of proteins, such as enzyme catalysis, are often understood from their crystallographic structures (1). On the other hand, it is crucial to take into account dynamic behavior to fully comprehend these functions (2, 3). In vivo, proteins are in constant motion among different conformations (3-5). The thermal energy, which is of the order of k B T per atom, where k B is the Boltzmann constant and T is the absolute temperature, triggers biomolecules to sample different conformations around the average structure. These conformations are also known as conformational substates (CSs) (5). Fluctuations among these CSs play an important role in protein function (3,5). These lead to the concept of a multidimensional potential energy landscape (EL) that specifies a complete description of CSs in proteins (6-9). The existence of an EL was proposed by H. Frauenfelder and others in the 1970s and has been validated both by computations and by experiments (6-12).Proteins show various dynamic phenomena over a wide range of timescales, from picoseconds to milliseconds (13). A fast dynamic process, on a timescale of a picosecond to 10 ns, also known as β-relaxation, occurs due to small amplitude fluctuations in atoms/ molecules, such as loop motions and side-chain rotations (14). The energy barrier or activation energy (E A ) between different CSs for this process is smaller than k B T (15). On t...

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Thermodynamics of the temperature‐induced unfolding of globular proteins

Cited by 52 publications

References 59 publications

Empirical free energy calculation: Comparison to calorimetric data

Empirical free energy calculation: Comparison to calorimetric data

AS‐48: a circular protein with an extremely stable globular structure

Effects of pressure on the dynamics of an oligomeric protein from deep-sea hyperthermophile

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