All the simulations were performed using the SHAKE algo-
rithm on hydrogen atoms, a 2 fs time step and Langevin dynamics
for temperature control.3.3 Enhanced
Molecular Dynamics
Methods
Once the system is prepared, minimized, and equilibrated, several
molecular dynamics methods can be applied and the choice
depends on the objective of the study (Table2). In theory, cMD
simulations can be envisaged to describe important biological pro-
cesses at atomic level such as the binding of the kinase inhibitor PP1
that reaches its binding site and finally reproduces the crystallo-
graphic binding pose in 15μs[24] and the millisecond-order
simulation of the reversible folding unfolding process of ubiquitin
[25]. However, such simulations require very powerful, specific
computer in order to be achieved in an acceptable time frame. To
overcome this limitation, a number of enhanced MD methods have
been developed where a bias is introduced into the simulation to
enhance the sampling of all the system, or along a phenomenon of
interest. A large number of biased methods, with a wide diversity of
possible bias have been developed during the past 30 years (see
Notes 3–5). Among them, the most used methods are temperature
replica exchange molecular dynamics [26], umbrella sampling
[27, 28], metadynamics [29, 30], scaled MD [31], and accelerated
molecular dynamics simulations [32, 33]. We can classify these
methods in two groups depending on whether the bias is added
along a reaction coordinate or not. In this case, the bias associated
to the reaction coordinate must represent the proper evolution of
the biological process of interest. Some methods such as REMD
and Simulated Annealing by their implemented algorithm produce
a simulation that is not time dependent but rather sampling
method, based on a Metropolis–Hastings algorithm.3.4 Accelerated
Molecular Dynamics
Method
3.4.1 Boost Potential
Accelerated molecular dynamics (aMD) method improves the con-
formational sampling by reducing energy barriers separating differ-
ent conformational states of a system. A boost potential is added to
bring up potential energy wells below a certain threshold level
(Ethr) without modifying those that are above [32]. As a result,
the magnitude of energy barriers is reduced, allowing the system to
sample conformational space that cannot be easily accessed by cMD
simulations [34]. It should be noted that the underlying shape of
the real potential is conserved so that the distribution of sampling
of different structures is still related to the original potential energy
distribution and can be recovered by a reweighing procedure.
When the potential condition is below the chosen threshold
Ethr, a boost potential,ΔVboost(r),is added to the original potential
energy,V 0 (r) whereris the atomic positions. The new modified
potential energyV(r)∗is defined as follows (seeNote 6):Enhanced Molecular Dynamics 409