In this regard, there are several challenges that emerge. The first is in choosing appropriate methods for computing bonded and nonbonded forces. In the context of bonded interactions, it is important to appropriately assign constraints. Many algorithms have been developed to constrain bond lengths. 8-10 A choice must be made in terms of which bonds are to be constrained. For most force fields, the constrained bonds are those involving hydrogen atoms, which have the fastest vibrational frequencies. Some force fields assume that all bonds are kept rigid. Misapplication of constraints can imbalance the force field model in subtle ways. If bonds are kept rigid when they are expected to oscillate, the parametrization of associated bonded terms (e.g., angles and dihedrals) may be compromised and introduce small but accumulating errors affecting conformational sampling. The user must also choose the appropriate settings for nonbonded calculations, specifically cutoffs. While these values are freely tunable in any MD simulation software, the values employed for truncation of Lennard-Jones (LJ) and electrostatic interactions are often fixed properties of the system that yield appropriate balance between the contributions of these forces to give an accurate intermolecular interaction energy. The particle mesh Ewald (PME) method 11 largely removes the requirement for strict adherence to a short-range electrostatic cutoff, but treatment of LJ terms may still be very sensitive to the choice of cutoff. The introduction of PME methods for computing LJ forces is an important development that will likely aid in resolving this issue. New users need to be aware that shortening cutoffs will speed up the simulation, but will almost certainly lead to a fast simulation with unreliable results.