How Well Can Simulation Predict Protein Folding Kinetics and Thermodynamics?

Snow, Christopher D.; Sorin, Eric J.; Rhee, Young Min; Pande, Vijay S.

doi:10.1146/annurev.biophys.34.040204.144447

Cited by 242 publications

(263 citation statements)

References 121 publications

(100 reference statements)

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“…Proteins such as barnase, 32 BPTI, 33 the engrailed homeodomain, 27 and the villin headpiece subdomain, 34 among others, 28,35,36 for which the denaturation mechanisms have been studied by computer simulations, do not exhibit complete elements of the secondary structure protected from solvent. Moreover, knowledge of the denaturation pathways of the LBDs may help to identify residues that are important for large-amplitude motions of the protein and, therefore, contributes to better understanding the molecular basis of the diseases caused by their mutations.…”

Section: Introductionmentioning

confidence: 99%

On the Denaturation Mechanisms of the Ligand Binding Domain of Thyroid Hormone Receptors

et al. 2009

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The ligand binding domain (LBD) of nuclear hormone receptors adopts a very compact, mostly R-helical structure that binds specific ligands with very high affinity. We use circular dichroism spectroscopy and high-temperature molecular dynamics simulations to investigate unfolding of the LBDs of thyroid hormone receptors (TRs). A molecular description of the denaturation mechanisms is obtained by molecular dynamics simulations of the TRR and TR LBDs in the absence and in the presence of the natural ligand Triac. The simulations show that the thermal unfolding of the LBD starts with the loss of native contacts and secondary structure elements, while the structure remains essentially compact, resembling a molten globule state. This differs from most protein denaturation simulations reported to date and suggests that the folding mechanism may start with the hydrophobic collapse of the TR LBDs. Our results reveal that the stabilities of the LBDs of the TRR and TR subtypes are affected to different degrees by the binding of the isoform selective ligand Triac and that ligand binding confers protection against thermal denaturation and unfolding in a subtype specific manner. Our simulations indicate two mechanisms by which the ligand stabilizes the LBD: (1) by enhancing the interactions between H8 and H11, and the interaction of the region between H1 and the Ω-loop with the core of the LBD, and (2) by shielding the hydrophobic H6 from hydration.

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Section: Introductionmentioning

confidence: 99%

On the Denaturation Mechanisms of the Ligand Binding Domain of Thyroid Hormone Receptors

et al. 2009

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“…It remains one of the most important and intriguing enzymes known to Man, representing the key plant enzyme involved in the first (and rate-limiting) step of the fixation of atmospheric CO 2 (Calvin cycle). It is also the world's most abundant enzyme, accounting for up to 30 -50% of the soluble leaf protein in C 4 and C 3 plants, respectively; suggesting that there is between 5-10 kg of Rubisco for every person on earth 2 converting on the order of 10 11 CO 2 per annum into organic material 1 . However, its abundance has been seen as direct result of its perceived inefficiency.…”

Section: Introductionmentioning

confidence: 99%

“…However, its abundance has been seen as direct result of its perceived inefficiency. 1,[3][4][5] This inefficiency is marked by two main observations: 1) low catalytic rate of carboxylation per active site (k cat ) (between 3-10 s -1 ) and 2) the competition between the dual functions of the enzyme in catalysing carboxylation (reacting with CO 2 ) relative to oxygenation (reacting with O 2 ), i.e. its specificity factor (τ) (ranging from 10 (purple photosynthetic bacteria) to 80 (C3 and C4 plants)) 6 , where (the V x corresponds to the maximum reaction velocity and the K x correspond to the Michaelis constants, where x is either CO 2 or O 2 ) 7 .…”

Section: Introductionmentioning

confidence: 99%

Comparative studies for evaluation of CO2 fixation in the cavity of the Rubisco enzyme using QM, QM/MM and linear-scaling DFT methods

2013

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We evaluate the minimum energy configuration (MM) and binding free energy (QM/MM and QM) of CO 2 to Rubisco, of fundamental importance to the carboxylation step of the reaction catalysed by Rubisco. Two structural motifs have been used to achieve this goal, one of which starts from the initial X-ray Protein Data Bank structure of Rubisco's active centre (671 atoms), and the other is a simplified, smaller model (77 atoms) which has been used most successfully, thus far, for study. The small model is subjected to quantum chemical Density functional theory (DFT) studies, both in vacuo and using implicit solvation. The effects of the protein environment are also included by means of a hybrid quantum mechanical/molecular mechanical (QM/MM) approach, using PM6/AMBER and B3LYP/AMBER schemes. Finally, linear-scaling DFT methods have also been applied to evaluate energetic features of the large motif, and the result obtained for the binding free energy of the CO 2 underlines the importance of the accurate modelling of the surrounding protein milieu using a full DFT description.

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“…[6][7][8] The difficulty arises from computing expectation values of observables from conformational excursions over a large number of degrees of freedom. Many methods have been devised to accelerate the exploration of phase space and improve convergence by smoothing the coarseness in the potential energy landscape while retaining sufficient resolution to accurately estimate the density of states.…”

Section: Introductionmentioning

confidence: 99%

Calculation of Protein Heat Capacity from Replica-Exchange Molecular Dynamics Simulations with Different Implicit Solvent Models

2008

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The heat capacity has played a major role in relating microscopic and macroscopic properties of proteins and their disorder-order phase transition of folding. Its calculation by atomistic simulation methods remains a significant challenge due to the complex and dynamic nature of protein structures, their solvent environment, and configurational averaging. To better understand these factors on calculating a protein heat capacity, we provide a comparative analysis of simulation models that differ in their implicit solvent description and forcefield resolution. Our model protein system is the src Homology 3 (SH3) domain of R-spectrin, and we report a series of 10 ns replica-exchange molecular dynamics simulations performed at temperatures ranging from 298 to 550 K, starting from the SH3 native structure. We apply the all-atom CHARMM22 force field with different modified analytical generalized Born solvent models (GBSW and GBMV2) and compare these simulation models with the distance-dependent dielectric screening of charge-charge interactions. A further comparison is provided with the united-atom CHARMM19 plus a pairwise GB model. Unfolding-folding transition temperatures of SH3 were estimated from the temperature-dependent profiles of the heat capacity, root-mean-square distance from the native structure, and the fraction of native contacts, each calculated from the density of states by using the weighted histogram analysis method. We observed that, for CHARMM22, the unfolding transition and energy probability density were quite sensitive to the implicit solvent description, in particular, the treatment of the protein-solvent dielectric boundary in GB models and their surface-areabased hydrophobic term. Among the solvent models tested, the calculated melting temperature varied in the range 353-438 K and was higher than the experimental value near 340 K. A reformulated GBMV2 model of employing a smoother molecular-volume dielectric interface was the most accurate in reproducing the native conformation and a two-state folding landscape, although the melting transition temperature did not show the smallest deviation from experiment. For the lower-resolution CHARMM19/GB model, the simulations failed to yield a bimodal energy distribution, yet the melting temperature was observed to be a good estimate of higher-resolution simulation models. We also demonstrate that a careful analysis of a relatively long simulation is necessary to avoid trapping in local minima and to find a true thermodynamic transition temperature.

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How Well Can Simulation Predict Protein Folding Kinetics and Thermodynamics?

Cited by 242 publications

References 121 publications

On the Denaturation Mechanisms of the Ligand Binding Domain of Thyroid Hormone Receptors

On the Denaturation Mechanisms of the Ligand Binding Domain of Thyroid Hormone Receptors

Comparative studies for evaluation of CO2 fixation in the cavity of the Rubisco enzyme using QM, QM/MM and linear-scaling DFT methods

Calculation of Protein Heat Capacity from Replica-Exchange Molecular Dynamics Simulations with Different Implicit Solvent Models

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