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An all-atom knowledge-based energy function for protein-DNA threading, docking decoy discrimination, and prediction of transcription-factor binding profiles.

ABSTRACT: How to make an accurate representation of protein-DNA interaction by an energy function is a long-standing unsolved problem in structural biology. Here, we modified a statistical potential based on the distance-scaled, finite ideal-gas reference state so that it is optimized for protein-DNA interactions. The changes include a volume-fraction correction to account for unmixable atom types in proteins and DNA in addition to the usage of a low-count correction, residue/base-specific atom types, and a shorter cutoff distance for protein-DNA interactions. The new statistical energy functions are tested in threading and docking decoy discriminations and prediction of protein-DNA binding affinities and transcription-factor binding profiles. The results indicate that new proposed energy functions are among the best in existing energy functions for protein-DNA interactions. The new energy functions are available as a web-server called DDNA 2.0 at http://sparks.informatics.iupui.edu. The server version was trained by the entire 212 protein-DNA complexes.

SUBMITTER: Xu B

PROVIDER: S-EPMC2743280 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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An all-atom knowledge-based energy function for protein-DNA threading, docking decoy discrimination, and prediction of transcription-factor binding profiles.

Xu Beisi B Yang Yuedong Y Liang Haojun H Zhou Yaoqi Y

Proteins 20090801 3

How to make an accurate representation of protein-DNA interaction by an energy function is a long-standing unsolved problem in structural biology. Here, we modified a statistical potential based on the distance-scaled, finite ideal-gas reference state so that it is optimized for protein-DNA interactions. The changes include a volume-fraction correction to account for unmixable atom types in proteins and DNA in addition to the usage of a low-count correction, residue/base-specific atom types, and ...[more]

PMID: 19274740

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Project description:Amyloid proteins are often associated with the onset of diseases, including Alzheimer's, Parkinson's and many others. However, there is a wide class of functional amyloids that are involved in physiological functions, e.g., formation of microbial biofilms or storage of hormones. Recent studies showed that an amyloid fibril could affect the aggregation of another protein, even from a different species. This may result in amplification or attenuation of the aggregation process. Insight into amyloid cross-interactions may be crucial for better understanding of amyloid diseases and the potential influence of microbial amyloids on human proteins. However, due to the demanding nature of the needed experiments, knowledge of such interactions is still limited. Here, we present PACT (Prediction of Amyloid Cross-interaction by Threading) - the computational method for the prediction of amyloid cross-interactions. The method is based on modeling of a heterogeneous fibril formed by two amyloidogenic peptides. The resulting structure is assessed by the structural statistical potential that approximates its plausibility and energetic stability. PACT was developed and first evaluated mostly on data collected in the AmyloGraph database of interacting amyloids and achieved high values of Area Under ROC (AUC=0.88) and F1 (0.82). Then, we applied our method to study the interactions of CsgA - a bacterial biofilm protein that was not used in our in-reference datasets, which is expressed in several bacterial species that inhabit the human intestines - with two human proteins. The study included alpha-synuclein, a human protein that is involved in Parkinson's disease, and human islet amyloid polypeptide (hIAPP), which is involved in type 2 diabetes. In both cases, PACT predicted the appearance of cross-interactions. Importantly, the method indicated specific regions of the proteins, which were shown to play a central role in both interactions. We experimentally confirmed the novel results of the indicated CsgA fragments interacting with hIAPP based on the kinetic characteristics obtained with the ThT assay. PACT opens the possibility of high-throughput studies of amyloid interactions. Importantly, it can work with fairly long protein fragments, and as a purely physicochemical approach, it relies very little on scarce training data. The tool is available as a web server at https://pact.e-science.pl/pact/ . The local version can be downloaded from https://github.com/KubaWojciechowski/PACT .

Dataset Information

An all-atom knowledge-based energy function for protein-DNA threading, docking decoy discrimination, and prediction of transcription-factor binding profiles.

Publications

An all-atom knowledge-based energy function for protein-DNA threading, docking decoy discrimination, and prediction of transcription-factor binding profiles.

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