CONTEXT: The low-density lipoprotein receptor (LDLR) regulates cholesterol uptake by mediating the hepatic clearance of plasma low-density lipoprotein cholesterol (LDL-C). Proprotein convertase subtilisin/kexin type-9 (PCSK9) attenuates LDLR function by binding to the LDLR, leading to its lysosomal degradation and preventing the total depletion of circulating LDL-C. However, pathogenic PCSK9 variants can reduce LDLR availability, significantly increase plasma LDL-C levels. Despite this understanding, the detailed molecular mechanism of LDLR-PCSK9 interaction remains unclear due to the incomplete LDLR structure. This study uses molecular dynamics (MD) simulations to predict LDLR structural dynamics upon binding to PCSK9. Furthermore, PCSK9 variants, E498A and R499G, that were identified in Malaysian FH patients were investigated for their mutational effects. Throughout the simulations, PCSK9 remained stable, while LDLR explored a larger conformational space. The LDLR-PCSK9 wild-type (WT) complex showed minimal changes, while the LDLR-PCSK9(R499G) complex exhibited pronounced conformational rearrangement. The MM/GBSA analysis revealed that the LDLR-PCSK9(E498A) complex had the highest binding affinity (- 63.81 kcal/mol), followed by the WT complex (- 33.07 kcal/mol), and LDLR-PCSK9(R499G) (- 24.21 kcal/mol). These findings offer novel insights into the dynamic interactions between LDLR and PCSK9, highlighting the role of structural flexibility in their relationship. Further MD simulation studies with the complete LDLR structure as well as experimental validation are needed to elucidate the molecular mechanisms underlying LDLR-PCSK9-mediated cholesterol homeostasis. METHODS: The initial structure of the wild-type (WT) LDLR-PCSK9 complex was obtained from PDB ID 3P5C, and the PCSK9 mutant structures (E498A and R499G) were modeled using the SPDBV program. MD simulations for each complex-LDLR-PCSK9 WT, LDLR-PCSK9(E498A), and LDLR-PCSK9(R499G)-were conducted using the GROMACS package with the CHARMM36m force field. The simulations were performed at 310.15 K with 2-fs timesteps under the isothermal-isobaric (NPT) ensemble, with each run lasting 500 ns. Including triplicates, the total duration of MD simulation time for all complexes amounted to 3.5 μs.