Pitfall in Quantum Mechanical/Molecular Mechanical
Molecular Dynamics Simulation of Small Solutes in Solution
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Abstract
Developments in computing hardware
and algorithms have made direct
molecular dynamics simulation with the combined quantum mechanical/molecular
mechanical methods affordable for small solute molecules in solution,
in which much improved accuracy can be obtained via the quantum mechanical
treatment of the solute molecule and even sometimes water molecules
in the first solvation shell. However, unlike the conventional molecular
mechanical simulations of large molecules, e.g., proteins, in solutions,
special care must be taken in the technical details of the simulation,
including the thermostat of the solute/solvent system, so that the
conformational space of the solute molecules can be properly sampled.
We show here that the common setup for classical molecular mechanical
molecular dynamics simulations, such as the Berendsen or single Nose–Hoover
thermostat, and/or rigid water models could lead to pathological sampling
of the solutes’ conformation. In the extreme example of a methanol
molecule in aqueous solution, improper and sluggish setups could generate
two peaks in the distribution of the O–H bond length. We discuss
the factors responsible for this somewhat unexpected result and evoke
a simple and ancient technical fix-up to resolve this problem