Dataset Information

HotPoint: hot spot prediction server for protein interfaces.

ABSTRACT: The energy distribution along the protein-protein interface is not homogenous; certain residues contribute more to the binding free energy, called 'hot spots'. Here, we present a web server, HotPoint, which predicts hot spots in protein interfaces using an empirical model. The empirical model incorporates a few simple rules consisting of occlusion from solvent and total knowledge-based pair potentials of residues. The prediction model is computationally efficient and achieves high accuracy of 70%. The input to the HotPoint server is a protein complex and two chain identifiers that form an interface. The server provides the hot spot prediction results, a table of residue properties and an interactive 3D visualization of the complex with hot spots highlighted. Results are also downloadable as text files. This web server can be used for analysis of any protein-protein interface which can be utilized by researchers working on binding sites characterization and rational design of small molecules for protein interactions. HotPoint is accessible at http://prism.ccbb.ku.edu.tr/hotpoint.

SUBMITTER: Tuncbag N

PROVIDER: S-EPMC2896123 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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HotPoint: hot spot prediction server for protein interfaces.

Tuncbag Nurcan N Keskin Ozlem O Gursoy Attila A

Nucleic acids research 20100505 Web Server issue

The energy distribution along the protein-protein interface is not homogenous; certain residues contribute more to the binding free energy, called 'hot spots'. Here, we present a web server, HotPoint, which predicts hot spots in protein interfaces using an empirical model. The empirical model incorporates a few simple rules consisting of occlusion from solvent and total knowledge-based pair potentials of residues. The prediction model is computationally efficient and achieves high accuracy of 70 ...[more]

PMID: 20444871

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Project description:BackgroundAlanine scanning mutagenesis is a powerful experimental methodology for investigating the structural and energetic characteristics of protein complexes. Individual amino-acids are systematically mutated to alanine and changes in free energy of binding (DeltaDeltaG) measured. Several experiments have shown that protein-protein interactions are critically dependent on just a few residues ("hot spots") at the interface. Hot spots make a dominant contribution to the free energy of binding and if mutated they can disrupt the interaction. As mutagenesis studies require significant experimental efforts, there is a need for accurate and reliable computational methods. Such methods would also add to our understanding of the determinants of affinity and specificity in protein-protein recognition.ResultsWe present a novel computational strategy to identify hot spot residues, given the structure of a complex. We consider the basic energetic terms that contribute to hot spot interactions, i.e. van der Waals potentials, solvation energy, hydrogen bonds and Coulomb electrostatics. We treat them as input features and use machine learning algorithms such as Support Vector Machines and Gaussian Processes to optimally combine and integrate them, based on a set of training examples of alanine mutations. We show that our approach is effective in predicting hot spots and it compares favourably to other available methods. In particular we find the best performances using Transductive Support Vector Machines, a semi-supervised learning scheme. When hot spots are defined as those residues for which DeltaDeltaG >or= 2 kcal/mol, our method achieves a precision and a recall respectively of 56% and 65%.ConclusionWe have developed an hybrid scheme in which energy terms are used as input features of machine learning models. This strategy combines the strengths of machine learning and energy-based methods. Although so far these two types of approaches have mainly been applied separately to biomolecular problems, the results of our investigation indicate that there are substantial benefits to be gained by their integration.

Project description:BackgroundProtein language models, inspired by the success of large language models in deciphering human language, have emerged as powerful tools for unraveling the intricate code of life inscribed within protein sequences. They have gained significant attention for their promising applications across various areas, including the sequence-based prediction of secondary and tertiary protein structure, the discovery of new functional protein sequences/folds, and the assessment of mutational impact on protein fitness. However, their utility in learning to predict protein residue properties based on scant datasets, such as protein-protein interaction (PPI)-hotspots whose mutations significantly impair PPIs, remained unclear. Here, we explore the feasibility of using protein language-learned representations as features for machine learning to predict PPI-hotspots using a dataset containing 414 experimentally confirmed PPI-hotspots and 504 PPI-nonhot spots.ResultsOur findings showcase the capacity of unsupervised learning with protein language models in capturing critical functional attributes of protein residues derived from the evolutionary information encoded within amino acid sequences. We show that methods relying on protein language models can compete with methods employing sequence and structure-based features to predict PPI-hotspots from the free protein structure. We observed an optimal number of features for model precision, suggesting a balance between information and overfitting.ConclusionsThis study underscores the potential of transformer-based protein language models to extract critical knowledge from sparse datasets, exemplified here by the challenging realm of predicting PPI-hotspots. These models offer a cost-effective and time-efficient alternative to traditional experimental methods for predicting certain residue properties. However, the challenge of explaining why specific features are important for determining certain residue properties remains.

Dataset Information

HotPoint: hot spot prediction server for protein interfaces.

Publications

HotPoint: hot spot prediction server for protein interfaces.

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