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The importance of hydrogen bonding between the glutamine side chains to the formation of amyloid VQIVYK parallel beta-sheets: an ONIOM DFT/AM1 study.

ABSTRACT: We report DFT calculations indicating that beta-sheet formation involving the capped amino acid sequence VQIVYK is due (at least in part) to cooperative H-bonding between the glutamine side chains. The sequence VQIVYK has been reported to be essential for the aggregation of the tau protein into the amyloids associated with Alzheimer's disease and has been crystallized. Sheets containing only capped Q's form cooperative H-bonds between the side chains that enhance stabilization while keeping the backbones of the individual strands close to the quasi-planarity expected for a beta-sheet. Sheets containing only capped A's cannot form H-bonds between the side chains, do not interact cooperatively, and form helical structures that deviate considerably from the quasi-planarity expected for beta-sheets. Comparisons between the sheets made from capped VQIVYK's, Q's, and A's illustrate the importance of the cooperative H-bonds between the Q's to the stability of tau amyloids.

SUBMITTER: Plumley JA

PROVIDER: S-EPMC2821795 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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The importance of hydrogen bonding between the glutamine side chains to the formation of amyloid VQIVYK parallel beta-sheets: an ONIOM DFT/AM1 study.

Plumley Joshua A JA Dannenberg J J JJ

Journal of the American Chemical Society 20100201 6

We report DFT calculations indicating that beta-sheet formation involving the capped amino acid sequence VQIVYK is due (at least in part) to cooperative H-bonding between the glutamine side chains. The sequence VQIVYK has been reported to be essential for the aggregation of the tau protein into the amyloids associated with Alzheimer's disease and has been crystallized. Sheets containing only capped Q's form cooperative H-bonds between the side chains that enhance stabilization while keeping the ...[more]

PMID: 20088582

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Project description:INTRODUCTION: The accurate packing of protein side chains is important for many computational biology problems, such as ab initio protein structure prediction, homology modelling, and protein design and ligand docking applications. Many of existing solutions are modelled as a computational optimisation problem. As well as the design of search algorithms, most solutions suffer from an inaccurate energy function for judging whether a prediction is good or bad. Even if the search has found the lowest energy, there is no certainty of obtaining the protein structures with correct side chains. METHODS: We present a side-chain modelling method, pacoPacker, which uses a parallel ant colony optimisation strategy based on sharing a single pheromone matrix. This parallel approach combines different sources of energy functions and generates protein side-chain conformations with the lowest energies jointly determined by the various energy functions. We further optimised the selected rotamers to construct subrotamer by rotamer minimisation, which reasonably improved the discreteness of the rotamer library. RESULTS: We focused on improving the accuracy of side-chain conformation prediction. For a testing set of 442 proteins, 87.19% of X1 and 77.11% of X12 angles were predicted correctly within 40° of the X-ray positions. We compared the accuracy of pacoPacker with state-of-the-art methods, such as CIS-RR and SCWRL4. We analysed the results from different perspectives, in terms of protein chain and individual residues. In this comprehensive benchmark testing, 51.5% of proteins within a length of 400 amino acids predicted by pacoPacker were superior to the results of CIS-RR and SCWRL4 simultaneously. Finally, we also showed the advantage of using the subrotamers strategy. All results confirmed that our parallel approach is competitive to state-of-the-art solutions for packing side chains. CONCLUSIONS: This parallel approach combines various sources of searching intelligence and energy functions to pack protein side chains. It provides a frame-work for combining different inaccuracy/usefulness objective functions by designing parallel heuristic search algorithms.

Project description:Alkylureas display hydrocarbon and amide groups, the primary functional groups of proteins. To obtain the thermodynamic information that is needed to analyze interactions of amides and proteins with nucleobases and nucleic acids, we quantify preferential interactions of alkylureas with nucleobases differing in the amount and composition of water-accessible surface area (ASA) by solubility assays. Using an established additive ASA-based analysis, we interpret these thermodynamic results to determine interactions of each alkylurea with five types of nucleobase unified atoms (carbonyl sp2O, amino sp3N, ring sp2N, methyl sp3C, and ring sp2C). All alkylureas interact favorably with nucleobase sp2C and sp3C atoms; these interactions become more favorable with an increasing level of alkylation of urea. Interactions with nucleobase sp2O are most favorable for urea, less favorable for methylurea and ethylurea, and unfavorable for dialkylated ureas. Contributions to overall alkylurea-nucleobase interactions from interactions with each nucleobase atom type are proportional to the ASA of that atom type with proportionality constant (interaction strength) ?, as observed previously for urea. Trends in ?-values for interactions of alkylureas with nucleobase atom types parallel those for corresponding amide compound atom types, offset because nucleobase ?-values are more favorable. Comparisons between ethylated and methylated ureas show interactions of amide compound sp3C with nucleobase sp2C, sp3C, sp2N, and sp3N atoms are favorable while amide sp3C-nucleobase sp2O interactions are unfavorable. Strongly favorable interactions of urea with nucleobase sp2O but weakly favorable interactions with nucleobase sp3N indicate that amide sp2N-nucleobase sp2O and nucleobase sp3N-amide sp2O hydrogen bonding (NH···O?C) interactions are favorable while amide sp2N-nucleobase sp3N interactions are unfavorable. These favorable amide-nucleobase hydrogen bonding interactions are prevalent in specific protein-nucleotide complexes.

Dataset Information

The importance of hydrogen bonding between the glutamine side chains to the formation of amyloid VQIVYK parallel beta-sheets: an ONIOM DFT/AM1 study.

Publications

The importance of hydrogen bonding between the glutamine side chains to the formation of amyloid VQIVYK parallel beta-sheets: an ONIOM DFT/AM1 study.

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