Volume 6 Supplement 1

9th German Conference on Chemoinformatics, GCC2013

Open Access

Balancing selectivity vs stability using molecular dynamics and umbrella sampling

  • Jeremie Mortier1Email author,
  • Elisabeth K Nyakatura1,
  • Markus Miettinen2,
  • Carsten Baldauf3,
  • Gerhard Wolber1 and
  • Beate Koksch1
Contributed equally
Journal of Cheminformatics20146(Suppl 1):O22

DOI: 10.1186/1758-2946-6-S1-O22

Published: 11 March 2014

Coiled coils are highly represented in biologically relevant macromolecules involved in important biological functions, such as gene expression regulation. The coiled coil environment has the great advantage to provide two very well defined intermolecular recognition surfaces. The peptide system VPE-VPK is a rationally designed heterodimeric coiled coil structure [1, 2]. The characteristic structure of the α-helical coiled coil allows randomizing the interaction partners of this dimeric system. Using a pool of VPE mutants that contains every possible combinations of the 20 canonical amino acids, specific binders could be searched empirically [1, 3]. In this work, three key positions in the hydrophobic core were randomized in a VPE phage displayed library (Figure 1).
Figure 1

VPE-VPK represented as (a) a helical wheel diagram and (b) a ribbon diagram, with randomized positions in yellow, and the directly interacting position in green.

This screen led to the identification of a novel core packing between VPE and VPK. One single consensus sequence was selected by the system, bearing a tyrosine in the hydrophobic core. Surprisingly, the dimer selected by phage display has a lower stability compared to the mother system. This important result raises the central question of selectivity vs stability. In order to address both aspects, theoretical investigations were conducted using molecular dynamics within the Gomacs suite. Pulling apart the two helices up to 3.00 nm from each other, potentials of mean force were calculated by umbrella sampling with a view to compare the energy barriers of the mother dimer to the phage display variant.


Authors’ Affiliations

Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin
Department of Physics, Freie Universität Berlin
Fritz Haber Institute


  1. Nyakatura EK, Reimann O, Vagt T, Salwiczek M, Koksch B: Accommodating fluorinated amino acids in a helical peptide environment. Rsc Adv. 2013, 3: 6319-6322. 10.1039/c3ra41110a.View ArticleGoogle Scholar
  2. Salwiczek M, Samsonov S, Vagt T, Nyakatura E, Fleige E, Numata J, et al: Position-dependent effects of fluorinated amino acids on the hydrophobic core formation of a heterodimeric coiled coil. Chemistry. 2009, 15: 7628-7636. 10.1002/chem.200802136.View ArticleGoogle Scholar
  3. Vagt T, Nyakatura E, Salwiczek M, Jäckel C, Koksch B: Towards identifying preferred interaction partners of fluorinated amino acids within the hydrophobic environment of a dimeric coiled coil peptide. Organic & biomolecular chemistry. 2010, 8: 1382-1386. 10.1039/b917205j.View ArticleGoogle Scholar


© Mortier et al; licensee Chemistry Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.