Enhanced sampling techniques in molecular dynamics simulations of biological systems

• Published in: Biochimica et biophysica acta Vol. 1850; no. 5; pp. 872 - 877
• Main Authors: Bernardi, Rafael C., Melo, Marcelo C.R., Schulten, Klaus
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2015
• Subjects: Algorithms; annealing; Carbohydrate Conformation; Carbohydrates - chemistry; Cellulosome; Cellulosomes - chemistry; chemical elements; Enhanced sampling; Generalized simulated annealing; Lipids - chemistry; Metadynamics; Molecular dynamics; Molecular Dynamics Simulation; Molecular Structure; Nucleic Acid Conformation; Nucleic Acids - chemistry; Nucleic Acids - metabolism; Protein Conformation; proteins; Proteins - chemistry; Proteins - metabolism; Replica-exchange molecular dynamics; Reproducibility of Results; research methods; Stochastic Processes; Structure-Activity Relationship; Surface Properties; Replica-exchange molecular dynamics; Molecular dynamics; Generalized simulated annealing; Cellulosome; Enhanced sampling; Metadynamics
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2014.10.019

Molecular dynamics has emerged as an important research methodology covering systems to the level of millions of atoms. However, insufficient sampling often limits its application. The limitation is due to rough energy landscapes, with many local minima separated by high-energy barriers, which govern the biomolecular motion. In the past few decades methods have been developed that address the sampling problem, such as replica-exchange molecular dynamics, metadynamics and simulated annealing. Here we present an overview over theses sampling methods in an attempt to shed light on which should be selected depending on the type of system property studied. Enhanced sampling methods have been employed for a broad range of biological systems and the choice of a suitable method is connected to biological and physical characteristics of the system, in particular system size. While metadynamics and replica-exchange molecular dynamics are the most adopted sampling methods to study biomolecular dynamics, simulated annealing is well suited to characterize very flexible systems. The use of annealing methods for a long time was restricted to simulation of small proteins; however, a variant of the method, generalized simulated annealing, can be employed at a relatively low computational cost to large macromolecular complexes. Molecular dynamics trajectories frequently do not reach all relevant conformational substates, for example those connected with biological function, a problem that can be addressed by employing enhanced sampling algorithms. This article is part of a Special Issue entitled Recent developments of molecular dynamics. [Display omitted] •Insufficient conformational sampling often limits molecular dynamics applications.•REMD and metadynamics allow a broader exploration of the energy surface.•GSA can be employed for large flexible macromolecular complexes.•GSA shows that a flexible linker in the cellulosome allows two preferential conformations.