calculations just like the main CPU on a laptop/desktop but with
higher computing performance [22].
The choice of the MD software and the simulation method
should be done in relation to hardware recommendations and
benchmarks. For AMBER software, the links for recommendations
and benchmarks are at http://ambermd.org/gpus/
recommended_hardware.htm and http://ambermd.org/gpus/
benchmarks.htmrespectively.2.2 Software As presented in Table1, a large number of software packages are
available for MD simulations. For the examples mentioned below,
we used AMBER suite as MD simulation software which is
distributed in two parts: AMBER, a proprietary software which
contains the codes of molecular dynamics calculations for CPUs
and GPUs (sander, pmemd, pmemd.cuda) and AmberTools, an
open source package that contains tools to parameterize organic
molecules and metal centers (antechamber), to prepare the system
(tleap, parmed), and to analyze trajectories (cpptraj, pytraj,
MMPBSA.py). Other indispensable tools can be found online, for
example to choose the number of replicas in the Temperature-
REMD simulation (http://folding.bmc.uu.se/remd/) or to pre-
dict protonation states of the biological system of interest at the
desired pH (PROPKA,http://propka.org/). These recommenda-
tions are generally given in the online tutorials that we strongly
advise to follow before launching a simulation (http://ambermd.
org/tutorials/). To visually display, analyze, and animate trajec-
tories, VMD is one of the appropriate programs, distributed free
of charge.
2.3 Studied
Biological System
For the two proposed protocols, we chose the human p38α
(MAPK14) kinase domain as a case study. The crystallographic
structure (pdb code: 3S3I), containing the biaryl-triazolopyridine
scaffold derivative in the ATP binding site, was chosen as a starting
structure for the simulations. The choice was based on the best
resolution of the p38αcrystallographic structures available in the
RCSB database [23] and the absence of sequence gaps in the 3D
structure.3 Methods
3.1 System
Preparation
All the scripts used in the simulations and analysis will be provided
in the supporting information. A molecular dynamics simulation
protocol always begins with the preparation of the system, which
consists of several steps:Enhanced Molecular Dynamics 407