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A hydrophobic spine stabilizes a surface-exposed ?-helix according to analysis of the solvent-accessible surface area.

ABSTRACT: Most of hydrophilic and hydrophobic residues are thought to be exposed and buried in proteins, respectively. In contrast to the majority of the existing studies on protein folding characteristics using protein structures, in this study, our aim was to design predictors for estimating relative solvent accessibility (RSA) of amino acid residues to discover protein folding characteristics from sequences.The proposed 20 real-value RSA predictors were designed on the basis of the support vector regression method with a set of informative physicochemical properties (PCPs) obtained by means of an optimal feature selection algorithm. Then, molecular dynamics simulations were performed for validating the knowledge discovered by analysis of the selected PCPs.The RSA predictors had the mean absolute error of 14.11% and a correlation coefficient of 0.69, better than the existing predictors. The hydrophilic-residue predictors preferred PCPs of buried amino acid residues to PCPs of exposed ones as prediction features. A hydrophobic spine composed of exposed hydrophobic residues of an ?-helix was discovered by analyzing the PCPs of RSA predictors corresponding to hydrophobic residues. For example, the results of a molecular dynamics simulation of wild-type sequences and their mutants showed that proteins 1MOF and 2WRP_H16I (Protein Data Bank IDs), which have a perfectly hydrophobic spine, have more stable structures than 1MOF_I54D and 2WRP do (which do not have a perfectly hydrophobic spine).We identified informative PCPs to design high-performance RSA predictors and to analyze these PCPs for identification of novel protein folding characteristics. A hydrophobic spine in a protein can help to stabilize exposed ?-helices.

SUBMITTER: Liou YF

PROVIDER: S-EPMC5259910 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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A hydrophobic spine stabilizes a surface-exposed α-helix according to analysis of the solvent-accessible surface area.

Liou Yi-Fan YF Huang Hui-Ling HL Ho Shinn-Ying SY

BMC bioinformatics 20161222 Suppl 19

<h4>Background</h4>Most of hydrophilic and hydrophobic residues are thought to be exposed and buried in proteins, respectively. In contrast to the majority of the existing studies on protein folding characteristics using protein structures, in this study, our aim was to design predictors for estimating relative solvent accessibility (RSA) of amino acid residues to discover protein folding characteristics from sequences.<h4>Methods</h4>The proposed 20 real-value RSA predictors were designed on th ...[more]

PMID: 28155647

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Project description:It is of great interest in modern drug design to accurately calculate the free energies of protein-ligand or nucleic acid-ligand binding. MM-PBSA (molecular mechanics Poisson-Boltzmann surface area) and MM-GBSA (molecular mechanics generalized Born surface area) have gained popularity in this field. For both methods, the conformational entropy, which is usually calculated through normal-mode analysis (NMA), is needed to calculate the absolute binding free energies. Unfortunately, NMA is computationally demanding and becomes a bottleneck of the MM-PB/GBSA-NMA methods. In this work, we have developed a fast approach to estimate the conformational entropy based upon solvent accessible surface area calculations. In our approach, the conformational entropy of a molecule, S, can be obtained by summing up the contributions of all atoms, no matter they are buried or exposed. Each atom has two types of surface areas, solvent accessible surface area (SAS) and buried SAS (BSAS). The two types of surface areas are weighted to estimate the contribution of an atom to S. Atoms having the same atom type share the same weight and a general parameter k is applied to balance the contributions of the two types of surface areas. This entropy model was parametrized using a large set of small molecules for which their conformational entropies were calculated at the B3LYP/6-31G* level taking the solvent effect into account. The weighted solvent accessible surface area (WSAS) model was extensively evaluated in three tests. For convenience, TS values, the product of temperature T and conformational entropy S, were calculated in those tests. T was always set to 298.15 K through the text. First of all, good correlations were achieved between WSAS TS and NMA TS for 44 protein or nucleic acid systems sampled with molecular dynamics simulations (10 snapshots were collected for postentropy calculations): the mean correlation coefficient squares (R²) was 0.56. As to the 20 complexes, the TS changes upon binding; T?S values were also calculated, and the mean R² was 0.67 between NMA and WSAS. In the second test, TS values were calculated for 12 proteins decoy sets (each set has 31 conformations) generated by the Rosetta software package. Again, good correlations were achieved for all decoy sets: the mean, maximum, and minimum of R² were 0.73, 0.89, and 0.55, respectively. Finally, binding free energies were calculated for 6 protein systems (the numbers of inhibitors range from 4 to 18) using four scoring functions. Compared to the measured binding free energies, the mean R² of the six protein systems were 0.51, 0.47, 0.40, and 0.43 for MM-GBSA-WSAS, MM-GBSA-NMA, MM-PBSA-WSAS, and MM-PBSA-NMA, respectively. The mean rms errors of prediction were 1.19, 1.24, 1.41, 1.29 kcal/mol for the four scoring functions, correspondingly. Therefore, the two scoring functions employing WSAS achieved a comparable prediction performance to that of the scoring functions using NMA. It should be emphasized that no minimization was performed prior to the WSAS calculation in the last test. Although WSAS is not as rigorous as physical models such as quasi-harmonic analysis and thermodynamic integration (TI), it is computationally very efficient as only surface area calculation is involved and no structural minimization is required. Moreover, WSAS has achieved a comparable performance to normal-mode analysis. We expect that this model could find its applications in the fields like high throughput screening (HTS), molecular docking, and rational protein design. In those fields, efficiency is crucial since there are a large number of compounds, docking poses, or protein models to be evaluated. A list of acronyms and abbreviations used in this work is provided for quick reference.

Project description:BACKGROUND: Protein structure prediction and computational protein design require efficient yet sufficiently accurate descriptions of aqueous solvent. We continue to evaluate the performance of the Coulomb/Accessible Surface Area (CASA) implicit solvent model, in combination with the Charmm19 molecular mechanics force field. We test a set of model parameters optimized earlier, and we also carry out a new optimization in this work, using as a target a set of experimental stability changes for single point mutations of various proteins and peptides. The optimization procedure is general, and could be used with other force fields. The computation of stability changes requires a model for the unfolded state of the protein. In our approach, this state is represented by tripeptide structures of the sequence Ala-X-Ala for each amino acid type X. We followed an iterative optimization scheme which, at each cycle, optimizes the solvation parameters and a set of tripeptide structures for the unfolded state. This protocol uses a set of 140 experimental stability mutations and a large set of tripeptide conformations to find the best tripeptide structures and solvation parameters. RESULTS: Using the optimized parameters, we obtain a mean unsigned error of 2.28 kcal/mol for the stability mutations. The performance of the CASA model is assessed by two further applications: (i) calculation of protein-ligand binding affinities and (ii) computational protein design. For these two applications, the previous parameters and the ones optimized here give a similar performance. For ligand binding, we obtain reasonable agreement with a set of 55 experimental mutation data, with a mean unsigned error of 1.76 kcal/mol with the new parameters and 1.47 kcal/mol with the earlier ones. We show that the optimized CASA model is not inferior to the Generalized Born/Surface Area (GB/SA) model for the prediction of these binding affinities. Likewise, the new parameters perform well for the design of 8 SH3 domain proteins where an average of 32.8% sequence identity relative to the native sequences was achieved. Further, it was shown that the computed sequences have the character of naturally-occuring homologues of the native sequences. CONCLUSION: Overall, the two CASA variants explored here perform very well for a wide variety of applications. Both variants provide an efficient solvent treatment for the computational engineering of ligands and proteins.

Dataset Information

A hydrophobic spine stabilizes a surface-exposed ?-helix according to analysis of the solvent-accessible surface area.

Publications

A hydrophobic spine stabilizes a surface-exposed α-helix according to analysis of the solvent-accessible surface area.

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