Protein structure prediction has reached the single-structure frontier.
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ABSTRACT:
SUBMITTER: Lane TJ
PROVIDER: S-EPMC9839224 | biostudies-literature | 2023 Feb
REPOSITORIES: biostudies-literature
Publications
Protein structure prediction has reached the single-structure frontier.
Nature methods 20230201 2
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Project description:Protein structure prediction has been greatly improved by deep learning in the past few years. However, the most successful methods rely on multiple sequence alignment (MSA) of the sequence homologs of the protein under prediction. In nature, a protein folds in the absence of its sequence homologs and thus, a MSA-free structure prediction method is desired. Here, we develop a single-sequence-based protein structure prediction method RaptorX-Single by integrating several protein language models and a structure generation module and then study its advantage over MSA-based methods. Our experimental results indicate that in addition to running much faster than MSA-based methods such as AlphaFold2, RaptorX-Single outperforms AlphaFold2 and other MSA-free methods in predicting the structure of antibodies (after fine-tuning on antibody data), proteins of very few sequence homologs, and single mutation effects. By comparing different protein language models, our results show that not only the scale but also the training data of protein language models will impact the performance. RaptorX-Single also compares favorably to MSA-based AlphaFold2 when the protein under prediction has a large number of sequence homologs.
| S-EPMC10990103 | biostudies-literature
Project description:We present the results for CAPRI Round 50, the fourth joint CASP-CAPRI protein assembly prediction challenge. The Round comprised a total of twelve targets, including six dimers, three trimers, and three higher-order oligomers. Four of these were easy targets, for which good structural templates were available either for the full assembly, or for the main interfaces (of the higher-order oligomers). Eight were difficult targets for which only distantly related templates were found for the individual subunits. Twenty-five CAPRI groups including eight automatic servers submitted ~1250 models per target. Twenty groups including six servers participated in the CAPRI scoring challenge submitted ~190 models per target. The accuracy of the predicted models was evaluated using the classical CAPRI criteria. The prediction performance was measured by a weighted scoring scheme that takes into account the number of models of acceptable quality or higher submitted by each group as part of their five top-ranking models. Compared to the previous CASP-CAPRI challenge, top performing groups submitted such models for a larger fraction (70-75%) of the targets in this Round, but fewer of these models were of high accuracy. Scorer groups achieved stronger performance with more groups submitting correct models for 70-80% of the targets or achieving high accuracy predictions. Servers performed less well in general, except for the MDOCKPP and LZERD servers, who performed on par with human groups. In addition to these results, major advances in methodology are discussed, providing an informative overview of where the prediction of protein assemblies currently stands.
| S-EPMC8616814 | biostudies-literature
Project description:AlphaFold2 and related computational systems predict protein structure using deep learning and co-evolutionary relationships encoded in multiple sequence alignments (MSAs). Despite high prediction accuracy achieved by these systems, challenges remain in (1) prediction of orphan and rapidly evolving proteins for which an MSA cannot be generated; (2) rapid exploration of designed structures; and (3) understanding the rules governing spontaneous polypeptide folding in solution. Here we report development of an end-to-end differentiable recurrent geometric network (RGN) that uses a protein language model (AminoBERT) to learn latent structural information from unaligned proteins. A linked geometric module compactly represents Cα backbone geometry in a translationally and rotationally invariant way. On average, RGN2 outperforms AlphaFold2 and RoseTTAFold on orphan proteins and classes of designed proteins while achieving up to a 106-fold reduction in compute time. These findings demonstrate the practical and theoretical strengths of protein language models relative to MSAs in structure prediction.
| S-EPMC10440047 | 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:Identifying protein thermodynamic stability changes upon single-point variants is crucial for studying mutation-induced alterations in protein biophysics, genomic variants, and mutation-related diseases. In the last decade, various computational methods have been developed to predict the effects of single-point variants, but the prediction accuracy is still far from satisfactory for practical applications. Herein, we review approaches and tools for predicting stability changes upon the single-point variant. Most of these methods require tertiary protein structure as input to achieve reliable predictions. However, the availability of protein structures limits the immediate application of these tools. To improve the performance of a computational prediction from a protein sequence without experimental structural information, we introduce a new computational framework: MU3DSP. This method assesses the effects of single-point variants on protein thermodynamic stability based on point mutated protein 3D structure profile. Given a protein sequence with a single variant as input, MU3DSP integrates both sequence-level features and averaged features of 3D structures obtained from sequence alignment to PDB to assess the change of thermodynamic stability induced by the substitution. MU3DSP outperforms existing methods on various benchmarks, making it a reliable tool to assess both somatic and germline substitution variants and assist in protein design. MU3DSP is available as an open-source tool at https://github.com/hurraygong/MU3DSP.
| S-EPMC9791599 | biostudies-literature
Project description:BackgroundThe accuracy of protein secondary structure prediction has been improving steadily towards the 88% estimated theoretical limit. There are two types of prediction algorithms: Single-sequence prediction algorithms imply that information about other (homologous) proteins is not available, while algorithms of the second type imply that information about homologous proteins is available, and use it intensively. The single-sequence algorithms could make an important contribution to studies of proteins with no detected homologs, however the accuracy of protein secondary structure prediction from a single-sequence is not as high as when the additional evolutionary information is present.ResultsIn this paper, we further refine and extend the hidden semi-Markov model (HSMM) initially considered in the BSPSS algorithm. We introduce an improved residue dependency model by considering the patterns of statistically significant amino acid correlation at structural segment borders. We also derive models that specialize on different sections of the dependency structure and incorporate them into HSMM. In addition, we implement an iterative training method to refine estimates of HSMM parameters. The three-state-per-residue accuracy and other accuracy measures of the new method, IPSSP, are shown to be comparable or better than ones for BSPSS as well as for PSIPRED, tested under the single-sequence condition.ConclusionsWe have shown that new dependency models and training methods bring further improvements to single-sequence protein secondary structure prediction. The results are obtained under cross-validation conditions using a dataset with no pair of sequences having significant sequence similarity. As new sequences are added to the database it is possible to augment the dependency structure and obtain even higher accuracy. Current and future advances should contribute to the improvement of function prediction for orphan proteins inscrutable to current similarity search methods.
| S-EPMC1479840 | biostudies-literature
Project description:A variety of non-biological structural motifs have been incorporated into the backbone of natural protein sequences. In parallel work, diverse unnatural oligomers of de novo design (termed "foldamers") have been developed that fold in defined ways. In this Perspective article, we survey foundational studies on protein backbone engineering, with a focus on alterations made in the context of complex tertiary folds. We go on to summarize recent work illustrating the potential promise of these methods to provide a general framework for the construction of foldamer mimics of protein tertiary structures.
| S-EPMC4211622 | 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:Studies have established that it is possible to differentiate between the brain's responses to observing correct and incorrect movements in navigation tasks. Furthermore, these classifications can be used as feedback for a learning-based BCI, to allow real or virtual robots to find quasi-optimal routes to a target. However, when navigating it is important not only to know we are moving in the right direction toward a target, but also to know when we have reached it. We asked participants to observe a virtual robot performing a 1-dimensional navigation task. We recorded EEG and then performed neurophysiological analysis on the responses to two classes of correct movements: those that moved closer to the target but did not reach it, and those that did reach the target. Further, we used a stepwise linear classifier on time-domain features to differentiate the classes on a single-trial basis. A second data set was also used to further test this single-trial classification. We found that the amplitude of the P300 was significantly greater in cases where the movement reached the target. Interestingly, we were able to classify the EEG signals evoked when observing the two classes of correct movements against each other with mean overall accuracy of 66.5 and 68.0% for the two data sets, with greater than chance levels of accuracy achieved for all participants. As a proof of concept, we have shown that it is possible to classify the EEG responses in observing these different correct movements against each other using single-trial EEG. This could be used as part of a learning-based BCI and opens a new door toward a more autonomous BCI navigation system.
| S-EPMC7027274 | biostudies-literature
Project description:Proteins have evolved to use water to help guide folding. A physically motivated, nonpairwise-additive model of water-mediated interactions added to a protein structure prediction Hamiltonian yields marked improvement in the quality of structure prediction for larger proteins. Free energy profile analysis suggests that long-range water-mediated potentials guide folding and smooth the underlying folding funnel. Analyzing simulation trajectories gives direct evidence that water-mediated interactions facilitate native-like packing of supersecondary structural elements. Long-range pairing of hydrophilic groups is an integral part of protein architecture. Specific water-mediated interactions are a universal feature of biomolecular recognition landscapes in both folding and binding.
| S-EPMC373465 | biostudies-literature