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Quantum mechanical studies on model alpha-pleated sheets.

ABSTRACT: Pauling and Corey proposed a pleated-sheet configuration, now called alpha-sheet, as one of the protein secondary structures in addition to alpha-helix and beta-sheet. Recently, it has been suggested that alpha-sheet is a common feature of amyloidogenic intermediates. We have investigated the stability of antiparallel beta-sheet and two conformations of alpha-sheet in solution phase using the density functional theoretical method. The peptides are modeled as two-strand acetyl-(Ala)(2)-N-methylamine. Using stages of geometry optimization and single point energy calculation at B3LYP/cc-pVTZ//B3LYP/6-31G* level and including zero-point energies, thermal, and entropic contribution, we have found that beta-sheet is the most stable conformation, while the alpha-sheet proposed by Pauling and Corey has 13.6 kcal/mol higher free energy than the beta-sheet. The alpha-sheet that resembles the structure observed in molecular dynamics simulations of amyloidogenic proteins at low pH becomes distorted after stages of geometry optimization in solution. Whether the alpha-sheets with longer chains would be increasingly favorable in water relative to the increase in internal energy of the chain needs further investigation. Different from the quantum mechanics results, AMBER parm94 force field gives small difference in solution phase energy between alpha-sheet and beta-sheet. The predicted amide I IR spectra of alpha-sheet shows the main band at higher frequency than beta-sheet.

SUBMITTER: Wu H

PROVIDER: S-EPMC2841717 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Quantum mechanical studies on model alpha-pleated sheets.

Wu Hao H Canfield Alana A Adhikari Jhashanath J Huo Shuanghong S

Journal of computational chemistry 20100401 6

Pauling and Corey proposed a pleated-sheet configuration, now called alpha-sheet, as one of the protein secondary structures in addition to alpha-helix and beta-sheet. Recently, it has been suggested that alpha-sheet is a common feature of amyloidogenic intermediates. We have investigated the stability of antiparallel beta-sheet and two conformations of alpha-sheet in solution phase using the density functional theoretical method. The peptides are modeled as two-strand acetyl-(Ala)(2)-N-methylam ...[more]

PMID: 19827141

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Project description:Two major techniques have been used to determine the three-dimensional structures of proteins: X-ray diffraction and NMR spectroscopy. In particular, the validation of NMR-derived protein structures is one of the most challenging problems in NMR spectroscopy. Therefore, researchers have proposed a plethora of methods to determine the accuracy and reliability of protein structures. Despite these proposals, there is a growing need for more sophisticated, physics-based structure validation methods. This approach will enable us to (a) characterize the "quality" of the NMR-derived ensemble as a whole by a single parameter, (b) unambiguously identify flaws in the sequence at a residue level, and (c) provide precise information, such as sets of backbone and side-chain torsional angles, that we can use to detect local flaws. Rather than reviewing all of the existing validation methods, this Account describes the contributions of our research group toward a solution of the long-standing problem of both global and local structure validation of NMR-derived protein structures. We emphasize a recently introduced physics-based methodology that makes use of observed and computed (13)C(alpha) chemical shifts (at the density functional theory (DFT) level of theory) for an accurate validation of protein structures in solution and in crystals. By assessing the ability of computed (13)C(alpha) chemical shifts to reproduce observed (13)C(alpha) chemical shifts of a single structure or ensemble of structures in solution and in crystals, we accomplish a global validation by using the conformationally averaged root-mean-square deviation, ca-rmsd, as a scoring function. In addition, the method enables us to provide local validation by identifying a set of individual amino acid conformations for which the computed and observed (13)C(alpha) chemical shifts do not agree within a certain error range and may represent a nonreliable fold of the protein model. Although it is computationally intensive, our validation method has several advantages, which we illustrate through a series of applications. This method makes use of the (13)C(alpha) chemical shifts, not shielding, that are ubiquitous to proteins and can be computed precisely from the phi, psi, and chi torsional angles. There is no need for a priori knowledge of the oligomeric state of the protein, and no knowledge-based information or additional NMR data are required. The primary limitation at this point is the computational cost of such calculations. However, we anticipate that enhancements in the speed of calculating these chemical shifts coupled with the ever-increasing computational power should soon make this a standard method accessible to the general NMR community.

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Quantum mechanical studies on model alpha-pleated sheets.

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Quantum mechanical studies on model alpha-pleated sheets.

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