Exploring LDLR-APOB Interactions in Familial Hypercholesterolemia in the Vietnamese Population: A Protein-Protein Docking Approach

Abstract

Atherosclerotic cardiovascular diseases (CVDs) are closely linked to factors such as familial hypercholesterolemia (FH), often caused by mutations in low-density lipoprotein receptor (LDLR) and apolipoprotein B (APOB). Through a comprehensive bioinformatic analysis, we identified novel LDLR and APOB mutations and their cardiovascular disease (CVD) implications, focusing on unique variants in the Vietnamese population. We used homology modeling to predict protein structures; in addition, through protein-protein molecular docking, we assessed how these mutations affect binding affinities. We identified 10 novel binding residues exclusive to the wild-type and precursor LDLR isoforms, including ASP-47, GLY-48, and GLU-51. Analyses of 154 complexes revealed 5 isoforms with low binding affinities and notable hydrogen-bonding interactions-APOB (Arg3527Trp)-LDLR (Cys318Arg), APOB (His3583Leu)-LDLR (Cys104Tyr), APOB wild-LDLR (Glu228Lys), APOB (Phe2469Cys)-LDLR (Glu288Lys), and APOB wild-LDLR (Ser130Ter). These results suggest strong and potentially detrimental interactions among these proteins. Furthermore, they highlight the molecular mechanisms underlying CVD development, reveal potential therapeutic targets, enhance our understanding of genetic variations, and could guide FH research.

Keywords: APOB; LDLR; familial hypercholesterolemia; homology modeling; interaction.

Figure 1.

Graphical representation of the study overview.

Figure 2.

Heatmap showing the binding affinities of complexes using colors. Low binding affinity complexes are represented in red, whereas highest binding affinity complexes are represented in blue.

Figure 3.

APOB-LDLR interaction sites. A docked complex of wild-type APOB-LDLR (showing interaction sites) is shown in (A). The closest poses of APOB and LDLR interactions are shown in (B) and (C). Deep salmon shade shows APOB, and teal represents LDLR; APOB-binding residues are shown in red, and LDLR-binding residues are displayed in orange. The interacting residues and respective bonds are highlighted in (D). Salt bridges are shown in red, and disulfide bonds are displayed in yellow; blue represents hydrogen bonds, and orange shows nonbonded contacts.

Figure 4.

LDLR-APOB (Arg1386Trp) interaction sites. Docked complex of LDLR-APOB (Arg1386Trp), showing interaction sites is shown in (A). The closest poses of APOB and LDLR interactions are shown in (B) and (C). Deep salmon shade shows the APOB, and teal represents the LDLR; APOB-binding residues are shown in red, and LDLR-binding residues are displayed in orange. The interacting residues and respective bonds are highlighted in (D). Salt bridges are shown in red, and disulfide bonds are shown in yellow; blue represents the hydrogen bonds, and orange depicts the nonbonded contacts.

Figure 5.

Visual representation of interacting hotspot residues of APOB and LDLR. (A) Deep salmon shade represents the APOB protein structure. Red represents the interacting hotspot residues of APOB, whereas blue represents the mutated residues. (B) Teal represents the APOB protein structure. Orange represents the interacting hotspot residues of APOB, whereas hot pink represents the mutated residues.