Table 1:

Computational methods used by studies reported in this review.

Acronym	Method	Synopsis	Application	Refs
QM/MM	Hybrid Quantum Mechanics / Molecular Mechanics	A subset of system simulated quantum mechanically (embedded in a larger MM environment) in order to allow bond breaking/formation, or to include molecules that cannot be adequately described by classical force fields	H+ transport	[21, 23, 24, 27]
			ATP hydrolysis	[31]
MS-RMD	Multiscale Reactive Molecular Dynamics	Using purposely derived reactive force field to treat bond breaking/formation	H+ transport	[21, 24–27]
CpHMD	Constant pH Molecular Dynamics	MD simulation allowing H+ exchange at specified sites (e.g., titratable protein side chain)	Determine pKa of residue and pH-induced conformational transition	[35]
MDFF	Molecular Dynamics Flexible Fitting	Structural refinement method that dynamically fits an atomic structure into experimentally determined electron densities	Refine low resolution molecular structure	[20]
FEP/TI	Free Energy Perturbation / Thermodynamic Integration	Calculate the energy difference between two related states by alchemically morphing one into the other	Calculate binding energy	[10, 14, 17–19, 45, 64, 68]
			determine residue pKa	[20]
SMD	Steered Molecular Dynamics	Applying a force or a moving restraint to bias the movement of a (group of) atom(s), either in real space or in collective variable space	Probe conformational transitions	[11, 20, 42–45]
			Drug unbinding	[62, 64]
US	Umbrella Sampling	Restraining the system at multiple points along a specified reaction coordinate to calculate the potential of mean force	Free energy calculations along specified reaction coordinate	[24–26, 30, 45, 54]
MetaD	Metadynamics	Calculate potential of mean force along a collective variable by inversely summing Gaussian potentials added during simulation to overcome energy barriers
aMD	Accelerated Molecular Dynamics	Enhanced sampling method where a biasing potential is applied to the dihedral and/or total potential of the system	Substrate binding	[40]
			Conformational change	[40, 41]
MSM	Markov State Model	Describe the kinetic of the process using the transition rates between different substates, typically calculated from very long or many discrete MD simulations	Ion release pathway	[16]
			Conformation change	[41, 49]
	String Method	Path search/optimization method to obtain a pathway connecting two states with a least barrier	Conformational change	[42, 45]
			Binding pathway	[64]
CG	Coarse Grained Simulation	Represent simulation systems with coarser particles, each representing a group of atoms	Lipid binding	[50, 53, 54]
	Molecular Docking	Predict ligand binding pose and energy to a target protein	Predict substrate binding	[40]
			Predict lipid/detergent binding	[48]
			Predict drug binding	[62, 67, 68]
	Ensemble Docking	An ensemble of protein structures (often derived from MD simulations) are used for ligand docking, to account for the dynamics of the docking receptor	Predict drug binding	[63, 66]