Using quantum mechanics to improve estimates of amino acid side chain rotamer energies

P. Douglas Renfrew, Glenn L. Butterfoss, Brian Kuhlman

Research output: Contribution to journalArticlepeer-review


Amino acid side chains adopt a discrete set of favorable conformations typically referred to as rotamers. The relative energies of rotamers partially determine which side chain conformations are more often observed in protein structures and accurate estimates of these energies are important for predicting protein structure and designing new proteins. Protein modelers typically calculate side chain rotamer energies by using molecular mechanics (MM) potentiab or by converting rotamer probabilities from the protein database (PDB) into relative free energies. One limitation of the knowledge-based energies is that rotamer preferences observed in the PDB can reflect internal side chain energies as well as longer-range interactions with the rest of the protein. Here, we test an alternative approach for calculating rotamer energies. We use three different quantum mechanics (QM) methods (second order Meller-Plesset (MP2), density functional theory (DFT) energy calculation using the B3LYP functional, and Hartree-Fock) to calculate the energy of amino acid rotamers in a dipeptide model system, and then use these pre-calculated values in side chain placement simulations. Energies were calculated for over 36,000 different conformations of leucine, isoleucine, and valine dipeptides with backbone torsion angles from the helical and strand regions of the Ramachandran plot. In a subset of cases these energies differ significantly from those calculated with standard molecular mechanics potentials or those derived from PDB statistics. We find that in these cases the energies from the QM methods result in more accurate placement of amino acid side chains in structure prediction tests.

Original languageEnglish (US)
Pages (from-to)1637-1646
Number of pages10
JournalProteins: Structure, Function and Genetics
Issue number4
StatePublished - Jun 2008


  • Computational protein design
  • Protein structure prediction
  • Rotamers
  • Torsion energies

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology


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