Influence of variation of a side chain on the folding equilibrium of a β‐peptide: Limitations of one‐step perturbation. Issue 22 (24th May 2013)

• Record Type: Journal Article
• Authors: Lin, Zhixiong; van Gunsteren, Wilfred F.
• Is Part Of: Journal of computational chemistry. Volume 34:Issue 22(2013)
• Page Start: 1899
• Page End: 1906
• Publication Date: 2013-05-24
• Subjects: Chemistry -- Data processing -- Periodicals; 542.85
• DOI: 10.1002/jcc.23331
• Languages: English
• ISSNs: 0192-8651

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>In a recent study (Lin et al., Helv. Chim. Acta 2011, <bold>94</bold>, 597), the one‐step perturbation method was applied to tackle a challenging computational problem, that is, the calculation of the folding free enthalpies Δ<italic>G</italic><sub>F, U</sub> of six hepta‐β‐peptides with different, Ala, Val, Leu, Ile, Ser, or Thr, side chains in the fifth residue. The Δ<italic>G</italic><sub>F, U</sub> values obtained using one‐step perturbation based on a single molecular dynamics simulation of a judiciously chosen reference state with soft‐core atoms in the side chain of the fifth residue showed an overall accuracy of about <italic>k</italic><sub>B</sub><italic>T</italic> for the four peptides with nonpolar side chains, but twice as large deviations were observed for the peptides with polar side chains. Here, alternative reference‐state Hamiltonians that better cover the conformational space relevant to these peptides are investigated, and post simulation rotational sampling of the χ<sub>1</sub> and χ<sub>2</sub> torsional angles of the fifth residue is carried out to sample different orientations of the side chain. A reference state with rather soft atoms yields accurate Δ<italic>G</italic><sub>F, U</sub> values for the peptides with the Ser and Thr side chains, but it failed to correctly predict the folding free enthalpy for one peptide with a nonpolar side chain, that is, Leu. Based on the results and those of earlier studies, possible ways to improve the accuracy of the efficient one‐step perturbation technique to compute free enthalpies of folding are discussed. © 2013 Wiley Periodicals, Inc.</p> </abstract>