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Changes in protein structure at the interface accompanying complex formation.

ABSTRACT: Protein interactions are essential in all biological processes. The changes brought about in the structure when a free component forms a complex with another molecule need to be characterized for a proper understanding of molecular recognition as well as for the successful implementation of docking algorithms. Here, unbound (U) and bound (B) forms of protein structures from the Protein-Protein Interaction Affinity Database are compared in order to enumerate the changes that occur at the interface atoms/residues in terms of the solvent-accessible surface area (ASA), secondary structure, temperature factors (B factors) and disorder-to-order transitions. It is found that the interface atoms optimize contacts with the atoms in the partner protein, which leads to an increase in their ASA in the bound interface in the majority (69%) of the proteins when compared with the unbound interface, and this is independent of the root-mean-square deviation between the U and B forms. Changes in secondary structure during the transition indicate a likely extension of helices and strands at the expense of turns and coils. A reduction in flexibility during complex formation is reflected in the decrease in B factors of the interface residues on going from the U form to the B form. There is, however, no distinction in flexibility between the interface and the surface in the monomeric structure, thereby highlighting the potential problem of using B factors for the prediction of binding sites in the unbound form for docking another protein. 16% of the proteins have missing (disordered) residues in the U form which are observed (ordered) in the B form, mostly with an irregular conformation; the data set also shows differences in the composition of interface and non-interface residues in the disordered polypeptide segments as well as differences in their surface burial.

SUBMITTER: Chakravarty D

PROVIDER: S-EPMC4645109 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Changes in protein structure at the interface accompanying complex formation.

Chakravarty Devlina D Janin Joël J Robert Charles H CH Chakrabarti Pinak P

IUCrJ 20151016 Pt 6

Protein interactions are essential in all biological processes. The changes brought about in the structure when a free component forms a complex with another molecule need to be characterized for a proper understanding of molecular recognition as well as for the successful implementation of docking algorithms. Here, unbound (U) and bound (B) forms of protein structures from the Protein-Protein Interaction Affinity Database are compared in order to enumerate the changes that occur at the interfac ...[more]

PMID: 26594372

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Project description:BackgroundIdentifying protein interfaces can inform how proteins interact with their binding partners, uncover the regulatory mechanisms that control biological functions and guide the development of novel therapeutic agents. A variety of computational approaches have been developed for predicting a protein's interfacial residues from its known sequence and structure. Methods using the known three-dimensional structures of proteins can be template-based or template-free. Template-based methods have limited success in predicting interfaces when homologues with known complex structures are not available to use as templates. The prediction performance of template-free methods that only rely only upon proteins' intrinsic properties is limited by the amount of biologically relevant features that can be included in an interface prediction model.ResultsWe describe the development of an integrated method for protein interface prediction (ISPIP) to explore the hypothesis that the efficacy of a computational prediction method of protein binding sites can be enhanced by using a combination of methods that rely on orthogonal structure-based properties of a query protein, combining and balancing both template-free and template-based features. ISPIP is a method that integrates these approaches through simple linear or logistic regression models and more complex decision tree models. On a diverse test set of 156 query proteins, ISPIP outperforms each of its individual classifiers in identifying protein binding interfaces.ConclusionsThe integrated method captures the best performance of individual classifiers and delivers an improved interface prediction. The method is robust and performs well even when one of the individual classifiers performs poorly on a particular query protein. This work demonstrates that integrating orthogonal methods that depend on different structural properties of proteins performs better at interface prediction than any individual classifier alone.

Project description:An active segment of the research community designing small molecules ("minimalist mimics" of peptide fragments) to interfere with protein-protein interactions have based their studies on an implicit hypothesis. Here we refer to this as the Secondary Structure Hypothesis, that might be defined as, "If a small molecule can orient amino acid side-chains in directions that resemble side-chains of the parent secondary structure at the interface, then that small molecule is a candidate to perturb the protein-protein interaction". Rigorous tests of this hypothesis require co-crystallization of minimalist mimics with protein receptors, and comparison of the bound conformations with the interface secondary structures they were designed to resemble. Unfortunately, to the best of our knowledge, there is no such analysis in the literature, and it is unlikely that enough examples will emerge in the near future to test the hypothesis. Research described here was designed to challenge this hypothesis from a different perspective. In a previous study, preferred conformations of a series of novel minimalist mimics were simulated then systematically overlaid on >240?000 crystallographically characterized protein-protein interfaces. Select data from that overlay procedure revealed chemotypes that overlay side chains on various PPI interfaces with a relatively high frequency of occurrence. The first aim of this work was to determine if good secondary structure mimics overlay frequently on PPI interfaces. The second aim of this work was to determine if overlays of preferred conformers at interface regions involve secondary structures. Thus situations where these conformations overlaid extremely well on PPI interfaces were analyzed to determine if secondary structures featured the PPI regions where these molecules overlaid in the previous study. Combining conclusions from these two studies enabled us to formulate a hypothesis that is complementary to the Secondary Structure Hypothesis, but, unlike this, is supported by abundant data. We call this the Interface Mimicry Hypothesis.

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Changes in protein structure at the interface accompanying complex formation.

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Changes in protein structure at the interface accompanying complex formation.

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