<div>Human cystathionine β-synthase (hCBS) is a unique pyridoxal 5'-phosphate (PLP) dependent enzyme that catalyses the condensation reactions in the transsulfuration pathways. The specific role of Heme in the enzymatic activities has not yet been established, however, several experimental studies indicated the bi-directional communications between the Heme and PLP. Performing classical molecular dynamics (MD) simulations upon developing the necessary force field parameters for the cysteine and

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... histidine bound hexa-coordinated Heme, we have investigated <i>In Silico</i> dynamical aspects of the bi-directional communications. Furthermore, we have investigated the comparative aspects of electron density overlap across the communicating pathways adopting the density functional theory (DFT) in conjunction with the hybrid exchange correlation functional for the CSB^WT (wild-type) and CBS^R266K (mutated) case. The atomistic dynamical simulations and subsequent explorations of the electronic structure not only confirm the reported observations but provide an in-depth mechanistic understating of how the non-covalent hydrogen bonding interactions with Cys52 control the such long-distance communication. Our study also provides a convincing answer to the reduced enzymatic activities in the R266K hCBS in comparison to the wild-type enzymes. We further realized that the difference in hydrogen-bonding patterns as well as salt-bridge interactions play the pivotal role in such long distant bi-directional communications.</div>