reaction of peptide bond is commonly observed. However, the detailed reaction pathway is

poorly understood.

In this study, the hydrolysis reaction of a peptide bond under different solution conditions,

namely, neutral and acidic pHs, was studied using a model compound N-methyl acetyl acrylamide

(N-MAA). Ab initio molecular dynamics combining statistical mechanics and quantum

mechanics was used to elucidate the reaction mechanism. Due to fuctuations at finite temperature

in solution, path sampling method was used to generate an ensemble of trajectories

according to their statistical weight in trajectory space. Car-Parrinello molecular dynamics was

applied to advance the time evolution of the reaction in collecting these representative trajectories.

Likelihood maximization was used to extract physically important degrees of freedom in

the system and approximations of the reaction coordinate were compared. It was found that this

hydrolysis reaction under both solution conditions is very complex in nature, which takes place

in a concerted fashion and involves many degrees of freedom. PB histograms were computed to

verify the results of reaction coordinate from likelihood maximization.

A coarse-grained model was developed to consider the surprisingly higher hydrolysis rate

for the peptide bonds in the hinge region of antibodies molecules. Free energy for breaking the

coarse-grained bond was calculated using umbrella sampling. The Bennett-Chandler procedure

was also used to calculate reaction rate constants. It was found that the fuctuations in the

system play an important role in determining the rate of breakage reaction. This may imply

that the special structure of antibodies could cause the enhanced hydrolytic rate over peptides.