Comparison of Three Chain-of-States Methods: Nudged Elastic Band and Replica Path with Restraints or Constraints

Chain-of-state methods are becoming important tools in studying the chemical reaction mechanisms, especially for biomacromolecules. In this article, three chain-of-state methods, the nudged elastic band (NEB) method and the replica path method with restraints or constraints, were tested and compared using three model systems with various sizes and at different levels of theory: alanine dipeptide isomerization, beta-alanine intramolecular condensation, and the matrix metalloproteinase 2 inhibition mechanism. The levels of theory used to describe the three model systems include molecular mechanics (MM), quantum mechanics (QM), and combined quantum mechanics and molecular mechanics (QM/MM). All three methods could correctly determine a reaction path with reasonable estimation of reaction barriers in most cases. The RMSD measurement with additional weighting schemes provides practically infinite choices of reaction coordinates to describe the reaction progress. These findings demonstrate that the chain-of-state methods are powerful tools when being used carefully to generate a plausible reaction mechanism with full pathway for complex systems at an affordable computational cost.