Effect of Pyridoxal Phosphate and L-Ser Bound on Human Serine Hydroxymethyltransferase By Molecular Dynamics Simulations

Abstract

Serine hydroxymethyltransferase (SHMT), a pyridoxal phosphate (PLP)-dependent enzyme, is involved in one-carbon metabolism. This enzyme catalyzes L-serine and tetrahydrofolate (THF) to glycine and 5,10-methylenetetrahydrofolate (5,10-CH₂-THF). In this study, molecular dynamics simulation was applied on wild-type human cytosolic SHMT (hcSHMT) tetramer in complex with PLP-Lys and L-ser in order to understand its structure and dynamics properties. The results, 1D- and 2D-RMSD plots versus simulation time of 100 ns suggest that the system reached the equilibrium at 30 ns, and thus the snapshots from the last 20 ns were extracted for analysis. The B-factor showed high stability of the whole tetramer in particular at the active site. The average per-residue decomposition free energy results showed the five key residues (S53, H148, S203, PLP-lys and R402) interacted with L-ser. Particularly, R402 had the strongest binding affinity (-10.09 kcal mol^-1) with L-ser. Additionally, the hydrogen bonding calculation provides residues of S53, S203, and K257 which indicates a strong H-bond with L-ser. PLP-lys (87%) had the strongest percentage of hydrogen bond. Thus, PLP-lys enzyme that catalyzes the reversible transfer of a carbon-unit from the L-serine to a second co-factor, the tetrahydrofolate (THF). The water accessibility at the active pocket observed by SASA calculation was around 68.25±18.83 Ų. These effects of wild-type hcSHMT with PLP-lys and L-ser bound can be used as the supporting evidence to understand the structure and dynamics of wild-type hcSHMT, which can now be used to develop inhibitors targeting SHMT and, therefore, antimalarial drugs.