Force field-based conformational searches: efficiency and performance for peptide receptor complexes

Abstract

Conformational search using force field methods on complex biomolecular systems is a key factor in understanding molecular and structural properties. The reliability of such investigations strongly depends on the efficiency of the conformational search algorithm as well as the accuracy of the employed force field. In the present work we compared the performance of two different approaches: the Monte-Carlo multiple minimum/low mode sampling (MCMM/LM), in combination with the OPLS2005 (MCMM/LM//OPLS2005), and Tabu-Search combined with Basin Hopping (TS/BH), employing the original OPLS-AA implementation proposed by Jorgensen (TS/BH//OPLS-AA). We investigated their performance in locating energetically low-lying structures and the efficiency in scanning the conformational phase space of non-covalently bonded complexes. As test systems we employed complexes of the artificial peptide receptor CBS-KKF with four different tetrapeptide ligands. The reliability and the accuracy of both approaches were examined by re-optimising all low-energy structures employing density functional theory with empirical dispersion correction in combination with triple zeta basis sets. Solvent effects were mimicked by a continuum solvent model. In all the four-test systems, the TS/BH//OPLS-AA approach yielded structures that are much lower in energy after the DFT optimisation. Additionally, it provided many low-lying structures that were not identified by the MCMM/LM//OPLS2005 approach.

Keywords:

• conformational search
• global optimisation
• force field
• DFT
• vibrational spectroscopy
• artificial peptide systems
• molecular recognition

Acknowledgements

We thank Jaeseung Hahn and Philipp Dierkes for their help with the MCMM/LM conformational searches. Financial support by the Deutsche Forschungsgemeinschaft within the framework of the GRK 1221 ‘Control of Electronic Properties of Assemblies of π-Conjugated Molecules’ and the research unit 1809 ‘Lichtinduzierte Dynamik in molekularen Aggregaten’ is gratefully acknowledged. We also acknowledge the financial support of the Volkswagen Stiftung.

Both authors contributed equally.

Notes

^aName of ligand carboxylates involved in complexation; for more information see text.

^bRelative energy with respect to the lowest-lying structure within the corresponding force field. Values in parentheses are re-optimised energies within the OPLS2005 (MacroModel) force field and given relative to the lowest-energy structure of MCMM/LM.

^cRelative energy with respect to the lowest-lying structure after re-optimisation of the force field structures with BP86-D3/COSMO/def2-TZVP.

^dDihedral angles Φ of the classification according to Moiani, illustration see Figure 3.

*Conformations, which do not agree with one of the four conformations as depicted in Figure 2, are marked with an asterisk. In these conformations the carbonyl and the adjacent NH-group are pointing in the same direction.

^#Convergence was not reached for the DFT geometry optimisation of the MC/LM structure 202_SC3b after 400 cycles (dE/dxyz = 8e-3; criterion: 1e-3).

^aRelative force field energy in kJ/mol.

^bAverage hydrogen bond distance in Å.

^cNumber of hydrogen bonds (n).

^dRelative DFT energy in kJ/mol.