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Conformational analysis of short polar side-chain amino-acids through umbrella sampling and DFT calculations

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Abstract

Molecular and quantum mechanics calculations were carried out in a series of tripeptides (GXG, where X = D, N and C) as models of the unfolded states of proteins. The selected central amino acids, especially aspartic acid (D) and asparagine (N) are known to present significant average conformations in partially allowed areas of the Ramachandran plot, which have been suggested to be important in unfolded protein regions. In this report, we present the calculation of the propensity values through an umbrella sampling procedure in combination with the calculation of the NMR J-coupling constants obtained by a DFT model. The experimental NMR observations can be reasonably explained in terms of a conformational distribution where PPII and β basins sum up propensities above 0.9. The conformational analysis of the side chain dihedral angle (χ1), along with the computation of 3J(HαHβ), revealed a preference for the g − and g + rotamers. These may be connected with the presence of intermolecular H-bonding and carbonyl–carbonyl interactions sampled in the PPII and β basins. Taking into account all those results, it can be established that these residues show a similar behavior to other amino acids in short peptides regarding backbone φ,ψ dihedral angle distribution, in agreement with some experimental analysis of capped dipeptides.

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Acknowledgments

Thanks are due to the CICYT (Ministerio de Economia y Competitividad) (Project MAT2012-36341) for financial support. This research was also funded by the CSIC (Consejo Superior de Investigaciones Científicas, Spain) under the Grant PIE-201360E097. J. R. acknowledges financial support through the Ramón y Cajal program (Contract RYC-2011-09585). The authors also thank the “Centro de Supercomputación de Galicia (CESGA)” and “Secretaria General Adjunta de Informatica (SGAI-CSIC)” for computational resources. We want to thank Prof. Schweitzer-Stenner, whose private comments some years ago motivated the present work. Computational support in the use of the distributed computing to the Ibercivis team is acknowledged (http://www.ibercivis.es). We are also very grateful to the anonymous citizens who have made available their desktop computers in an altruistic way.

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  1. Biophym, Instituto de Estructura de la Materia, CSIC, Serrano 113-bis, 28006, Madrid, Spain

    Javier Ramos & Victor L. Cruz

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  1. Javier Ramos
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  2. Victor L. Cruz
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Correspondence to Victor L. Cruz.

Electronic supplementary material

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Online Resource 1

Relative free energy map for GDG tripeptide using the Charmm27 force field. Energies are given in kT units and angles in degrees. (PDF 168 kb)

Online Resource 2

List of initial and final φ, ψ values corresponding to the fully optimized geometries for each tripeptide. The last column corresponds to the optimized electronic energies in atomic units. Figure showing the distribution of the optimized geometries in a Ramachandran plot (PDF 72 kb)

Online Resource 3

List of φ, ψ, χ 1 , and J-coupling constants calculated for the GDG case. Similar values were obtained for GNG. (PDF 97 kb)

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Ramos, J., Cruz, V.L. Conformational analysis of short polar side-chain amino-acids through umbrella sampling and DFT calculations. J Mol Model 22, 273 (2016). https://doi.org/10.1007/s00894-016-3139-1

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