Predicting Catalytic Proton Donors and Nucleophiles in Enzymes: How Adding Dynamics Helps Elucidate the Structure-Function Relationships.

ABSTRACT: Despite the relevance of understanding structure-function relationships, robust prediction of proton donors and nucleophiles in enzyme active sites remains challenging. Here we tested three types of state-of-the-art computational methods to calculate the p K_a's of the buried and hydrogen bonded catalytic dyads in five enzymes. We asked the question what determines the p K_a order, i.e., what makes a residue proton donor vs a nucleophile. The continuous constant pH molecular dynamics simulations captured the experimental p K_a orders and revealed that the negative nucleophile is stabilized by increased hydrogen bonding and solvent exposure as compared to the proton donor. Surprisingly, this simple trend is not apparent from crystal structures and the static st

SUBMITTER: Huang Y 

PROVIDER: S-EPMC6555141 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature