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WIREs Comput Mol Sci
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Molecular ‘time‐machines’ to unravel key biological events for drug design

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Molecular dynamics (MD) has become a routine tool in structural biology and structure‐based drug design (SBDD). MD offers extraordinary insights into the structures and dynamics of biological systems. With the current capabilities of high‐performance supercomputers, it is now possible to perform MD simulations of systems as large as millions of atoms and for several nanoseconds timescale. Nevertheless, many complicated molecular mechanisms, including ligand binding/unbinding and protein folding, usually take place on timescales of several microseconds to milliseconds, which are beyond the practical limits of standard MD simulations. Such issues with traditional MD approaches can be effectively tackled with new generation MD methods, such as enhanced sampling MD approaches and coarse‐grained MD (CG‐MD) scheme. The former employ a bias to steer the simulations and reveal biological events that are usually very slow, while the latter groups atoms as interaction beads, thereby reducing the system size and facilitating longer MD simulations that can witness large conformational changes in biological systems. In this review, we outline many of such advanced MD methods, and discuss how their applications are providing significant insights into important biological processes, particularly those relevant to drug design and discovery. WIREs Comput Mol Sci 2017, 7:e1306. doi: 10.1002/wcms.1306

A schematic representation of a metadynamics protocol. The figure shows that a mock system (in yellow color) is initially trapped in a local minimum. During metadynamics, the Gaussian potentials (Gaussians shown in blue) are added to the energy wells, such that the system reaches the first saddle point only to fall into the next energy well. This process is iterated until all possible energetic wells are filled with Gaussians, thus leading to a flat energy surface.
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A mock system shown as an all‐atom model and a coarse‐grained (CG)‐model (a). A comparison of an all‐atom model (shown as stick representation) and a residue‐based CG‐model (shown as bead representation) of the protein–protein complex of a HIV envelop glycoprotein (gp120 shown in red) and a CD4 receptor (displayed in blue) (b).
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A comprehensive 3D model (a) of a voltage‐gated sodium ion channel (ribbon representation in red) embedded in a lipid bilayer (as bead representation in blue) and immersed in a water box. A sodium ion (shown as yellow spheres) is being pulled out of the channel using steered molecular dynamics (SMD) (b) and the force profile for the pulling of the ion during SMD simulation (c) is also shown. The peak represents the high‐energy barrier in the ion permeation pathway, while the plateau indicates that there are not huge barriers for the ion passage during the respective duration of the SMD simulation.
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Schematic diagrams describing the process of constant force steered molecular dynamics (SMD) (a), constant velocity SMD (b), and random acceleration molecular dynamics (RAMD) (c). In the constant force SMD (cf‐SMD) scheme (a), a pre‐selected force is applied on the ligand and pulled in a pre‐selected direction. In the constant velocity SMD (cv‐SMD) scheme (b), the ligand is pulled out the protein, in a defined direction, with a chosen constant velocity and spring constant and the force profile for the entire reaction coordinate is obtained. In RAMD (c), a pre‐determined force is applied on the ligand and pulled out of the protein in a random direction. Unlike SMD, in RAMD, the direction of exit is automatically chosen on the fly.
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A schematic representation of a replica‐exchange molecular dynamics (REMD) protocol (a). At a defined time intervals, the energy of the structures (shown as mock shapes in different colors) of the replicas are evaluated. If the energy from run 1 is lower than that of the structure from run 2, then replicas are exchanged. In the event of an exchange, the structure from run 1 is now simulated at temperature 2, while the structure run 2 is simulated at temperature 1. If the exchange does not occur, then the simulation continues at the same temperature. The mock figure displaying the potential energy exchanges made during the course of an REMD simulation (b) is provided, along with a zoom‐in figure of a single exchange (c).
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Software > Simulation Methods
Simulation Methods > Free Energy Methods
Structure and Mechanism > Computational Biochemistry and Biophysics

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