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EnCPdock: a web-interface for direct conjoint comparative analyses of complementarity and binding energetics in inter-protein associations

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Abstract

Context

Protein–protein interaction (PPI) is a key component linked to virtually all cellular processes. Be it an enzyme catalysis (‘classic type functions’ of proteins) or a signal transduction (‘non-classic’), proteins generally function involving stable or quasi-stable multi-protein associations. The physical basis for such associations is inherent in the combined effect of shape and electrostatic complementarities (Sc, EC) of the interacting protein partners at their interface, which provides indirect probabilistic estimates of the stability and affinity of the interaction. While Sc is a necessary criterion for inter-protein associations, EC can be favorable as well as disfavored (e.g., in transient interactions). Estimating equilibrium thermodynamic parameters (∆Gbinding, Kd) by experimental means is costly and time consuming, thereby opening windows for computational structural interventions. Attempts to empirically probe ∆Gbinding from coarse-grain structural descriptors (primarily, surface area based terms) have lately been overtaken by physics-based, knowledge-based and their hybrid approaches (MM/PBSA, FoldX, etc.) that directly compute ∆Gbinding without involving intermediate structural descriptors.

Methods

Here, we present EnCPdock (https://www.scinetmol.in/EnCPdock/), a user-friendly web-interface for the direct conjoint comparative analyses of complementarity and binding energetics in proteins. EnCPdock returns an AI-predicted ∆Gbinding computed by combining complementarity (Sc, EC) and other high-level structural descriptors (input feature vectors), and renders a prediction accuracy comparable to the state-of-the-art. EnCPdock further locates a PPI complex in terms of its {Sc, EC} values (taken as an ordered pair) in the two-dimensional complementarity plot (CP). In addition, it also generates mobile molecular graphics of the interfacial atomic contact network for further analyses. EnCPdock also furnishes individual feature trends along with the relative probability estimates (Prfmax) of the obtained feature-scores with respect to the events of their highest observed frequencies. Together, these functionalities are of real practical use for structural tinkering and intervention as might be relevant in the design of targeted protein-interfaces. Combining all its features and applications, EnCPdock presents a unique online tool that should be beneficial to structural biologists and researchers across related fraternities.

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Data availability

Relevant tracking information for all entries in all datasets used can be found in the online Supplementary Material. Over and above this, any specific data that might be required can be made accessible on request.

Notes

  1. Dissociation constant.

  2. (Gibbs) Free energy of binding.

  3. Molecular Mechanics combined with Poisson–Boltzmann electrostatics and accessible surface area estimates.

  4. Molecular Mechanics combined with Generalized Born electrostatics and accessible surface area estimates.

  5. SD: standard deviations.

  6. Receptor and ligand each consisting of a single polypeptide chain.

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Acknowledgements

We convey our sincerest gratitude to Prof. Dhananjay Bhattacharyya (Saha Institute of Nuclear Physics, Kolkata, India, retired) for his time and thoughts on the matter in the course of one extremely helpful discussion during the revision.

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Authors and Affiliations

  1. Department of Chemistry and Structural Biology, Weizmann Institute of Science, 7610001, Rehovot, Israel

    Gargi Biswas

  2. Institute of Molecular Biology gGmbH (IMB), Ackermannweg 4, 55128, Mainz, Germany

    Debasish Mukherjee

  3. Dept of Biochemical Engineering, Faculty of Engineering Science, University College London, London, WC1E 6BT, UK

    Nalok Dutta

  4. Department of Botany, Narajole Raj College, Vidyasagar University, Midnapore, 721211, India

    Prithwi Ghosh

  5. Department of Microbiology, Asutosh College (affiliated with University of Calcutta), 92, Shyama Prasad Mukherjee Rd, Bhowanipore, 700026, Kolkata, India

    Sankar Basu

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S.B. conceptualized the idea, designed the calculations, and wrote the main manuscript with help from G.B., N.D., and D.M. developed the web-server with assistance from S.B. N.D., and P.G. did the required literature survey. G.B. performed all training, validations, and actively participated in drafting the results and discussion. All the authors participated during the revisions, read, and approved the final manuscript.

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Correspondence to Sankar Basu.

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Biswas, G., Mukherjee, D., Dutta, N. et al. EnCPdock: a web-interface for direct conjoint comparative analyses of complementarity and binding energetics in inter-protein associations. J Mol Model 29, 239 (2023). https://doi.org/10.1007/s00894-023-05626-0

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