Molecular Modeling of Proteins

Volume 1215 of the series Methods in Molecular Biology pp 151-171


Tackling Sampling Challenges in Biomolecular Simulations

  • Alessandro BarducciAffiliated withLaboratory of Statistical Biophysics, School of Basic Sciences, Ecole Polytechnique Fédérale de Lausanne
  • , Jim PfaendtnerAffiliated withDepartment of Chemical Engineering, University of Washington
  • , Massimiliano BonomiAffiliated withDepartment of Chemistry, University of Cambridge Email author 

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Molecular dynamics (MD) simulations are a powerful tool to give an atomistic insight into the structure and dynamics of proteins. However, the time scales accessible in standard simulations, which often do not match those in which interesting biological processes occur, limit their predictive capabilities. Many advanced sampling techniques have been proposed over the years to overcome this limitation. This chapter focuses on metadynamics, a method based on the introduction of a time-dependent bias potential to accelerate sampling and recover equilibrium properties of a few descriptors that are able to capture the complexity of a process at a coarse-grained level. The theory of metadynamics and its combination with other popular sampling techniques such as the replica exchange method is briefly presented. Practical applications of these techniques to the study of the Trp-Cage miniprotein folding are also illustrated. The examples contain a guide for performing these calculations with PLUMED, a plugin to perform enhanced sampling simulations in combination with many popular MD codes.

Key words

Enhanced sampling Metadynamics PLUMED Replica exchange methods Molecular dynamics Collective variables Free energy