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Rules of Physical Mathematics Govern Intrinsically Disordered Proteins.

ABSTRACT: In stark contrast to foldable proteins with a unique folded state, intrinsically disordered proteins and regions (IDPs) persist in perpetually disordered ensembles. Yet an IDP ensemble has conformational features-even when averaged-that are specific to its sequence. In fact, subtle changes in an IDP sequence can modulate its conformational features and its function. Recent advances in theoretical physics reveal a set of elegant mathematical expressions that describe the intricate relationships among IDP sequences, their ensemble conformations, and the regulation of their biological functions. These equations also describe the molecular properties of IDP sequences that predict similarities and dissimilarities in their functions and facilitate classification of sequences by function, an unmet challenge to traditional bioinformatics. These physical sequence-patterning metrics offer a promising new avenue for advancing synthetic biology at a time when multiple novel functional modes mediated by IDPs are emerging.

SUBMITTER: Ghosh K

PROVIDER: S-EPMC9190209 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Rules of Physical Mathematics Govern Intrinsically Disordered Proteins.

Ghosh Kingshuk K Huihui Jonathan J Phillips Michael M Haider Austin A

Annual review of biophysics 20220204

In stark contrast to foldable proteins with a unique folded state, intrinsically disordered proteins and regions (IDPs) persist in perpetually disordered ensembles. Yet an IDP ensemble has conformational features-even when averaged-that are specific to its sequence. In fact, subtle changes in an IDP sequence can modulate its conformational features and its function. Recent advances in theoretical physics reveal a set of elegant mathematical expressions that describe the intricate relationships a ...[more]

PMID: 35119946

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Project description:BackgroundProteins are composed of one or more amino acid chains and exhibit several structure levels. IDPs (intrinsically disordered proteins) represent a class of proteins that do not fold into any particular conformation and exist as dynamic ensembles in their native state. Due to their intrinsic adaptability, IDPs participate in many regulatory biological processes, including parasite immune escape. Using the information from trypanosomatids proteomes, we developed a pipeline for the identification, characterization and analysis of IDPs. The pipeline employs six disorder prediction methodologies and integrates structural and functional annotation information, subcellular location prediction and physicochemical properties. At the core of the IDP pipeline, there is a relational database that describes the protein disorder knowledge in a logically consistent manner.ResultsThe results obtained from the IDP pipeline showed that Leishmania and Trypanosoma species have approximately 70% and 55% IDPs, respectively. Our results indicate that IDPs in trypanosomatids contain disorder-promoting amino acids and order-promoting amino acids. The functional annotation analysis demonstrated enrichment of selected Gene Ontology terms. A relevant association was observed between the disordered residue numbers within predicted IDPs and their subcellular location, lack of transmembrane domains and lack of predicted function. We validated our computational findings with 2D electrophoresis designed for IDP identification and found that 100% of the identified protein spots were predicted in silico.ConclusionsBecause there is no pipeline or database addressing IDPs in trypanosomatids, the pipeline described here represents the first attempt to establish possible correlations between protein function and structural disorder in these eukaryotes. Interestingly, all significant associations detected in the contingency analysis were observed when the protein disorder content reached approximately 40%. The exploratory data analysis allowed us to develop hypotheses regarding the IDPs' association with key biological features of these parasites, including transcription and transcriptional regulation, RNA processing and splicing, and cytoskeleton.

Dataset Information

Rules of Physical Mathematics Govern Intrinsically Disordered Proteins.

Publications

Rules of Physical Mathematics Govern Intrinsically Disordered Proteins.

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