Balancing Accuracy and Cost of Confinement Simulations by Interpolation and Extrapolation of Confinement Energies

• Published in: Journal of chemical theory and computation Vol. 12; no. 6; pp. 2779 - 2789
• Main Authors: Villemot, François, Capelli, Riccardo, Colombo, Giorgio, van der Vaart, Arjan
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 14.06.2016
• Subjects: Accuracy; Alanine - chemistry; Computer simulation; Confinement; Extrapolation; Free energy; Interpolation; Lactoferrin - chemistry; Lactoferrin - metabolism; Mathematical analysis; Models, Molecular; Peptides - chemistry; Peptides - metabolism; Protein Structure, Tertiary; Sampling; Thermodynamics
• ISSN: 1549-9618; 1549-9626
• DOI: 10.1021/acs.jctc.5b01183

Improvements to the confinement method for the calculation of conformational free energy differences are presented. By taking advantage of phase space overlap between simulations at different frequencies, significant gains in accuracy and speed are reached. The optimal frequency spacing for the simulations is obtained from extrapolations of the confinement energy, and relaxation time analysis is used to determine time steps, simulation lengths, and friction coefficients. At postprocessing, interpolation of confinement energies is used to significantly reduce discretization errors in the calculation of conformational free energies. The efficiency of this protocol is illustrated by applications to alanine n-peptides and lactoferricin. For the alanine-n-peptide, errors were reduced between 2- and 10-fold and sampling times between 8- and 67-fold, while for lactoferricin the long sampling times at low frequencies were reduced 10–100-fold.