A three-state prediction of single point mutations on protein stability changes.
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ABSTRACT:
SUBMITTER: Capriotti E
PROVIDER: S-EPMC2323669 | biostudies-literature | 2008
REPOSITORIES: biostudies-literature
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A three-state prediction of single point mutations on protein stability changes.
Capriotti Emidio E Fariselli Piero P Rossi Ivan I Casadio Rita R
BMC bioinformatics 20080326
<h4>Background</h4>A basic question of protein structural studies is to which extent mutations affect the stability. This question may be addressed starting from sequence and/or from structure. In proteomics and genomics studies prediction of protein stability free energy change (DeltaDeltaG) upon single point mutation may also help the annotation process. The experimental DeltaDeltaG values are affected by uncertainty as measured by standard deviations. Most of the DeltaDeltaG values are nearly ...[more]
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Project description:Accurate prediction of protein stability changes resulting from amino acid substitutions is of utmost importance in medicine to better understand which mutations are deleterious, leading to diseases, and which are neutral. Since conducting wet lab experiments to get a better understanding of protein mutations is costly and time consuming, and because of huge number of possible mutations the need of computational methods that could accurately predict effects of amino acid mutations is of greatest importance. In this research, we present a robust methodology to predict the energy changes of a proteins upon mutations. The proposed prediction scheme is based on two step algorithm that is a Holdout Random Sampler followed by a neural network model for regression. The Holdout Random Sampler is utilized to analysis the energy change, the corresponding uncertainty, and to obtain a set of admissible energy changes, expressed as a cumulative distribution function. These values are further utilized to train a simple neural network model that can predict the energy changes. Results were blindly tested (validated) against experimental energy changes, giving Pearson correlation coefficients of 0.66 for Single Point Mutations and 0.77 for Multiple Point Mutations. These results confirm the successfulness of our method, since it outperforms majority of previous studies in this field.
| S-EPMC7023245 | biostudies-literature
Project description:MotivationMutations in human genome are mainly through single nucleotide polymorphism, some of which can affect stability and function of proteins, causing human diseases. Several methods have been proposed to predict the effect of mutations on protein stability; but most require features from experimental structure. Given the fast progress in protein structure prediction, this work explores the possibility to improve the mutation-induced stability change prediction using low-resolution structure modeling.ResultsWe developed a new method (STRUM) for predicting stability change caused by single-point mutations. Starting from wild-type sequences, 3D models are constructed by the iterative threading assembly refinement (I-TASSER) simulations, where physics- and knowledge-based energy functions are derived on the I-TASSER models and used to train STRUM models through gradient boosting regression. STRUM was assessed by 5-fold cross validation on 3421 experimentally determined mutations from 150 proteins. The Pearson correlation coefficient (PCC) between predicted and measured changes of Gibbs free-energy gap, ΔΔG, upon mutation reaches 0.79 with a root-mean-square error 1.2 kcal/mol in the mutation-based cross-validations. The PCC reduces if separating training and test mutations from non-homologous proteins, which reflects inherent correlations in the current mutation sample. Nevertheless, the results significantly outperform other state-of-the-art methods, including those built on experimental protein structures. Detailed analyses show that the most sensitive features in STRUM are the physics-based energy terms on I-TASSER models and the conservation scores from multiple-threading template alignments. However, the ΔΔG prediction accuracy has only a marginal dependence on the accuracy of protein structure models as long as the global fold is correct. These data demonstrate the feasibility to use low-resolution structure modeling for high-accuracy stability change prediction upon point mutations.Availability and implementationhttp://zhanglab.ccmb.med.umich.edu/STRUM/ CONTACT: qiang@suda.edu.cn and zhng@umich.eduSupplementary informationSupplementary data are available at Bioinformatics online.
| S-EPMC5039926 | biostudies-literature
Project description:BackgroundPredicting the effect of single point variations on protein stability constitutes a crucial step toward understanding the relationship between protein structure and function. To this end, several methods have been developed to predict changes in the Gibbs free energy of unfolding (∆∆G) between wild type and variant proteins, using sequence and structure information. Most of the available methods however do not exhibit the anti-symmetric prediction property, which guarantees that the predicted ∆∆G value for a variation is the exact opposite of that predicted for the reverse variation, i.e., ∆∆G(A → B) = -∆∆G(B → A), where A and B are amino acids.ResultsHere we introduce simple anti-symmetric features, based on evolutionary information, which are combined to define an untrained method, DDGun (DDG untrained). DDGun is a simple approach based on evolutionary information that predicts the ∆∆G for single and multiple variations from sequence and structure information (DDGun3D). Our method achieves remarkable performance without any training on the experimental datasets, reaching Pearson correlation coefficients between predicted and measured ∆∆G values of ~ 0.5 and ~ 0.4 for single and multiple site variations, respectively. Surprisingly, DDGun performances are comparable with those of state of the art methods. DDGun also naturally predicts multiple site variations, thereby defining a benchmark method for both single site and multiple site predictors. DDGun is anti-symmetric by construction predicting the value of the ∆∆G of a reciprocal variation as almost equal (depending on the sequence profile) to -∆∆G of the direct variation. This is a valuable property that is missing in the majority of the methods.ConclusionsEvolutionary information alone combined in an untrained method can achieve remarkably high performances in the prediction of ∆∆G upon protein mutation. Non-trained approaches like DDGun represent a valid benchmark both for scoring the predictive power of the individual features and for assessing the learning capability of supervised methods.
| S-EPMC6606456 | biostudies-literature
Project description:BackgroundPoint mutations can have a strong impact on protein stability. A change in stability may subsequently lead to dysfunction and finally cause diseases. Moreover, protein engineering approaches aim to deliberately modify protein properties, where stability is a major constraint. In order to support basic research and protein design tasks, several computational tools for predicting the change in stability upon mutations have been developed. Comparative studies have shown the usefulness but also limitations of such programs.ResultsWe aim to contribute a novel method for predicting changes in stability upon point mutation in proteins called MAESTRO. MAESTRO is structure based and distinguishes itself from similar approaches in the following points: (i) MAESTRO implements a multi-agent machine learning system. (ii) It also provides predicted free energy change (Δ ΔG) values and a corresponding prediction confidence estimation. (iii) It provides high throughput scanning for multi-point mutations where sites and types of mutation can be comprehensively controlled. (iv) Finally, the software provides a specific mode for the prediction of stabilizing disulfide bonds. The predictive power of MAESTRO for single point mutations and stabilizing disulfide bonds is comparable to similar methods.ConclusionsMAESTRO is a versatile tool in the field of stability change prediction upon point mutations. Executables for the Linux and Windows operating systems are freely available to non-commercial users from http://biwww.che.sbg.ac.at/MAESTRO.
| S-EPMC4403899 | biostudies-literature
Project description:Predicting the effect of missense variations on protein stability and dynamics is important for understanding their role in diseases, and the link between protein structure and function. Approaches to estimate these changes have been proposed, but most only consider single-point missense variants and a static state of the protein, with those that incorporate dynamics are computationally expensive. Here we present DynaMut2, a web server that combines Normal Mode Analysis (NMA) methods to capture protein motion and our graph-based signatures to represent the wildtype environment to investigate the effects of single and multiple point mutations on protein stability and dynamics. DynaMut2 was able to accurately predict the effects of missense mutations on protein stability, achieving Pearson's correlation of up to 0.72 (RMSE: 1.02 kcal/mol) on a single point and 0.64 (RMSE: 1.80 kcal/mol) on multiple-point missense mutations across 10-fold cross-validation and independent blind tests. For single-point mutations, DynaMut2 achieved comparable performance with other methods when predicting variations in Gibbs Free Energy (ΔΔG) and in melting temperature (ΔTm ). We anticipate our tool to be a valuable suite for the study of protein flexibility analysis and the study of the role of variants in disease. DynaMut2 is freely available as a web server and API at http://biosig.unimelb.edu.au/dynamut2.
| S-EPMC7737773 | biostudies-literature
Project description:The accurate prediction of the impact of an amino acid substitution on the thermal stability of a protein is a central issue in protein science, and is of key relevance for the rational optimization of various bioprocesses that use enzymes in unusual conditions. Here we present one of the first computational tools to predict the change in melting temperature ΔTm upon point mutations, given the protein structure and, when available, the melting temperature Tm of the wild-type protein. The key ingredients of our model structure are standard and temperature-dependent statistical potentials, which are combined with the help of an artificial neural network. The model structure was chosen on the basis of a detailed thermodynamic analysis of the system. The parameters of the model were identified on a set of more than 1,600 mutations with experimentally measured ΔTm. The performance of our method was tested using a strict 5-fold cross-validation procedure, and was found to be significantly superior to that of competing methods. We obtained a root mean square deviation between predicted and experimental ΔTm values of 4.2 °C that reduces to 2.9 °C when ten percent outliers are removed. A webserver-based tool is freely available for non-commercial use at soft.dezyme.com.
| S-EPMC4796876 | biostudies-other
Project description:Understanding the effects of missense mutations on protein stability is a widely acknowledged significant biological problem. Genomic missense mutations may alter one or more amino acids, leading to increased or decreased stability of the encoded proteins. In this study, we describe a novel approach-Protein Stability Prediction with a Gaussian Network Model (PSP-GNM)-to measure the unfolding Gibbs free energy change (ΔΔG) and evaluate the effects of single amino acid substitutions on protein stability. Specifically, PSP-GNM employs a coarse-grained Gaussian Network Model (GNM) that has interactions between amino acids weighted by the Miyazawa-Jernigan statistical potential. We used PSP-GNM to simulate partial unfolding of the wildtype and mutant protein structures, and then used the difference in the energies and entropies of the unfolded wildtype and mutant proteins to calculate ΔΔG. The extent of the agreement between the ΔΔG calculated by PSP-GNM and the experimental ΔΔG was evaluated on three benchmark datasets: 350 forward mutations (S350 dataset), 669 forward and reverse mutations (S669 dataset) and 611 forward and reverse mutations (S611 dataset). We observed a Pearson correlation coefficient as high as 0.61, which is comparable to many of the existing state-of-the-art methods. The agreement with experimental ΔΔG further increased when we considered only those measurements made close to 25 °C and neutral pH, suggesting dependence on experimental conditions. We also assessed for the antisymmetry (ΔΔGreverse = -ΔΔGforward) between the forward and reverse mutations on the Ssym+ dataset, which has 352 forward and reverse mutations. While most available methods do not display significant antisymmetry, PSP-GNM demonstrated near-perfect antisymmetry, with a Pearson correlation of -0.97. PSP-GNM is written in Python and can be downloaded as a stand-alone code.
| S-EPMC9505940 | biostudies-literature
Project description:BACKGROUND: Protein stabilities can be affected sometimes by point mutations introduced to the protein. Current sequence-information-based protein stability prediction encoding schemes of machine learning approaches include sparse encoding and amino acid property encoding. Property encoding schemes employ physical-chemical information of the mutated protein environments, however, they produce complexity in the mean time when many properties joined in the scheme. The complexity introduces noises that affect machine learning algorithm accuracies. In order to overcome the problem we described a new encoding scheme that graded twenty amino acids into groups according to their specific property values. RESULTS: We employed three predefined values, 0.1, 0.5, and 0.9 to represent 'weak', 'middle', and 'strong' groups for each amino acid property, and introduced two thresholds for each property to split twenty amino acids into one of the three groups according to their property values. Each amino acid can take only one out of three predefined values rather than twenty different values for each property. The complexity and noises in the encoding schemes were reduced in this way. More than 7% average accuracy improvement was found in the graded amino acid property encoding schemes by 20-fold cross validation. The overall accuracy of our method is more than 72% when performed on the independent test sets starting from sequence information with three-state prediction definitions. CONCLUSIONS: Grading numeric values of amino acid property can reduce the noises and complexity of input information. It is in accordance with biochemical concepts for amino acid properties and makes the input data simplified in the mean time. The idea of graded property encoding schemes may be applied to protein related predictions with machine learning approaches.
| S-EPMC3820156 | biostudies-literature
Project description:Thermostability issue of protein point mutations is a common occurrence in protein engineering. An application which predicts the thermostability of mutants can be helpful for guiding decision making process in protein design via mutagenesis. An in silico point mutation scanning method is frequently used to find "hot spots" in proteins for focused mutagenesis. ProTherm (http://gibk26.bio.kyutech.ac.jp/jouhou/Protherm/protherm.html) is a public database that consists of thousands of protein mutants' experimentally measured thermostability. Two data sets based on two differently measured thermostability properties of protein single point mutations, namely the unfolding free energy change (ddG) and melting temperature change (dTm) were obtained from this database. Folding free energy change calculation from Rosetta, structural information of the point mutations as well as amino acid physical properties were obtained for building thermostability prediction models with informatics modeling tools. Five supervised machine learning methods (support vector machine, random forests, artificial neural network, naïve Bayes classifier, K nearest neighbor) and partial least squares regression are used for building the prediction models. Binary and ternary classifications as well as regression models were built and evaluated. Data set redundancy and balancing, the reverse mutations technique, feature selection, and comparison to other published methods were discussed. Rosetta calculated folding free energy change ranked as the most influential features in all prediction models. Other descriptors also made significant contributions to increasing the accuracy of the prediction models.
| S-EPMC4567301 | biostudies-literature
Project description:MOTIVATION:The folding free energy is an important characteristic of proteins stability and is directly related to protein's wild-type function. The changes of protein's stability due to naturally occurring mutations, missense mutations, are typically causing diseases. Single point mutations made in vitro are frequently used to assess the contribution of given amino acid to the stability of the protein. In both cases, it is desirable to predict the change of the folding free energy upon single point mutations in order to either provide insights of the molecular mechanism of the change or to design new experimental studies. RESULTS:We report an approach that predicts the free energy change upon single point mutation by utilizing the 3D structure of the wild-type protein. It is based on variation of the molecular mechanics Generalized Born (MMGB) method, scaled with optimized parameters (sMMGB) and utilizing specific model of unfolded state. The corresponding mutations are built in silico and the predictions are tested against large dataset of 1109 mutations with experimentally measured changes of the folding free energy. Benchmarking resulted in root mean square deviation = 1.78 kcal/mol and slope of the linear regression fit between the experimental data and the calculations was 1.04. The sMMGB is compared with other leading methods of predicting folding free energy changes upon single mutations and results discussed with respect to various parameters. AVAILABILITY:All the pdb files we used in this article can be downloaded from http://compbio.clemson.edu/downloadDir/mentaldisorders/sMMGB_pdb.rar. SUPPLEMENTARY INFORMATION:Supplementary data are available at Bioinformatics online.
| S-EPMC3289912 | biostudies-literature