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Effective approach for calculations of absolute stability of proteins using focused dielectric constants.

ABSTRACT: The ability to predict the absolute stability of proteins based on their corresponding sequence and structure is a problem of great fundamental and practical importance. In this work, we report an extensive, refinement and validation of our recent approach (Roca et al., FEBS Lett 2007;581:2065-2071) for predicting absolute values of protein stability DeltaG(fold). This approach employs the semimacroscopic protein dipole Langevin dipole method in its linear response approximation version (PDLD/S-LRA) while using the best fitted values of the dielectric constants epsilon'(p) and epsilon'(eff) for the self energy and charge-charge interactions, respectively. The method is validated on a diverse set of 45 proteins. It is found that the best fitted values of both dielectric constants are around 40. However, the self energy of internal residues and the charge-charge interactions of Lys have to be treated with care, using a somewhat lower values of epsilon'(p) and epsilon'(eff). The predictions of DeltaG(fold) reported here, have an average error of only 1.8 kcal/mole compared to the observed values, making our method very promising for estimating protein stability. It also provides valuable insight into the complex electrostatic phenomena taking place in folded proteins.

SUBMITTER: Vicatos S

PROVIDER: S-EPMC4505752 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Effective approach for calculations of absolute stability of proteins using focused dielectric constants.

Vicatos Spyridon S Roca Maite M Warshel Arieh A

Proteins 20091101 3

The ability to predict the absolute stability of proteins based on their corresponding sequence and structure is a problem of great fundamental and practical importance. In this work, we report an extensive, refinement and validation of our recent approach (Roca et al., FEBS Lett 2007;581:2065-2071) for predicting absolute values of protein stability DeltaG(fold). This approach employs the semimacroscopic protein dipole Langevin dipole method in its linear response approximation version (PDLD/S- ...[more]

PMID: 19856460

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Project description:The absolute (standard) binding free energy of eight FK506-related ligands to FKBP12 is calculated using free energy perturbation molecular dynamics (FEP/MD) simulations with explicit solvent. A number of features are implemented to improve the accuracy and enhance the convergence of the calculations. First, the absolute binding free energy is decomposed into sequential steps during which the ligand-surrounding interactions as well as various biasing potentials restraining the translation, orientation, and conformation of the ligand are turned "on" and "off." Second, sampling of the ligand conformation is enforced by a restraining potential based on the root mean-square deviation relative to the bound state conformation. The effect of all the restraining potentials is rigorously unbiased, and it is shown explicitly that the final results are independent of all artificial restraints. Third, the repulsive and dispersive free energy contribution arising from the Lennard-Jones interactions of the ligand with its surrounding (protein and solvent) is calculated using the Weeks-Chandler-Andersen separation. This separation also improves convergence of the FEP/MD calculations. Fourth, to decrease the computational cost, only a small number of atoms in the vicinity of the binding site are simulated explicitly, while all the influence of the remaining atoms is incorporated implicitly using the generalized solvent boundary potential (GSBP) method. With GSBP, the size of the simulated FKBP12/ligand systems is significantly reduced, from approximately 25,000 to 2500. The computations are very efficient and the statistical error is small ( approximately 1 kcal/mol). The calculated binding free energies are generally in good agreement with available experimental data and previous calculations (within approximately 2 kcal/mol). The present results indicate that a strategy based on FEP/MD simulations of a reduced GSBP atomic model sampled with conformational, translational, and orientational restraining potentials can be computationally inexpensive and accurate.

Project description:BACKGROUND:Digital food registration via online platforms that are coupled to large food databases obviates the need for manual processing of dietary data. The reliability of such platforms depends on the quality of the associated food database. OBJECTIVE:In this study, we validate the database of MyFitnessPal versus the Belgian food composition database, Nubel. METHODS:After carefully given instructions, 50 participants used MyFitnessPal to each complete a 4-day dietary record 2 times (T1 and T2), with 1 month in between T1 and T2. Nutrient intake values were calculated either manually, using the food composition database Nubel, or automatically, using the database coupled to MyFitnessPal. First, nutrient values from T1 were used as a training set to develop an algorithm that defined upper limit values for energy intake, carbohydrates, fat, protein, fiber, sugar, cholesterol, and sodium. These limits were applied to the MyFitnessPal dataset extracted at T2 to remove extremely high and likely erroneous values. Original and cleaned T2 values were correlated with the Nubel calculated values. Bias was estimated using Bland-Altman plots. Finally, we simulated the impact of using MyFitnessPal for nutrient analysis instead of Nubel on the power of a study design that correlates nutrient intake to a chosen outcome variable. RESULTS:Per food portion, the following upper limits were defined: 1500 kilocalories for total energy intake, 95 grams (g) for carbohydrates, 92 g for fat, 52 g for protein, 22 g for fiber, 70 g for sugar, 600 mg for cholesterol, and 3600 mg for sodium. Cleaning the dataset extracted at T2 resulted in a 2.8% rejection. Cleaned MyFitnessPal values demonstrated strong correlations with Nubel for energy intake (r=0.96), carbohydrates (r=0.90), fat (r=0.90), protein (r=0.90), fiber (r=0.80), and sugar (r=0.79), but weak correlations for cholesterol (?=0.51) and sodium (?=0.53); all P values were ?.001. No bias was found between both methods, except for a fixed bias for fiber and a proportional bias for cholesterol. A 5-10% power loss should be taken into account when correlating energy intake and macronutrients obtained with MyFitnessPal to an outcome variable, compared to Nubel. CONCLUSIONS:Dietary analysis with MyFitnessPal is accurate and efficient for total energy intake, macronutrients, sugar, and fiber, but not for cholesterol and sodium.

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Effective approach for calculations of absolute stability of proteins using focused dielectric constants.

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Effective approach for calculations of absolute stability of proteins using focused dielectric constants.

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