Conformational Changes during High Temperature Simulations

Limiting Conformational Changes during High Temperature Simulations 

High temperature searches of conformational space (see Quenched Dynamics on page 78), can produce unwanted conformational changes, such as cis-trans peptide flips, ring inversions, and other changes that you cannot reverse easily by geometry optimization. You can use restraints to prevent these changes. 

Restraints can facilitate docking a substrate molecule to a binding site. Restraints can also facilitate the interaction of two molecules in solution. In both cases, it is unlikely that two different neutral molecules would come into van der Waals contact with each other without the use of restraints. 

Example If a drug molecule interacts with a receptor molecule through hydrogen bonds, then you might restrain the distance between the donor and acceptor atoms involved in the hydrogen bonds. During a molecular dynamics simulation, these atoms would stay near an ideal value, while the rest of the molecular system fully relaxes. 

Example You could explore the possible geometries of two molecules interacting in solution and guess at initial transition structures. For example, if molecule Aundergoes nucleophilic attack on molecule B, you could impose a distance restraint between the two atoms that would form a bond, allowing the rest of the system to relax. Simulations such as these can help to explain stereochemistry or reaction kinetics and can serve as starting points for quantum mechanics calculations and optimizations. 

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