Bound Phospholipids Assist Cholesteryl Ester Transfer in the Cholesteryl Ester Transfer Protein.

Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that assists the transfer of cholesteryl esters (CEs) from antiatherogenic high-density lipoproteins (HDLs) to proatherogenic low-density lipoproteins (LDLs), initiating cholesterol plaques in the arteries. Consequently, inhibiting the activity of CETP is therefore being pursued as a novel strategy to reduce the risk of cardiovascular diseases (CVDs). The crystal structure of CETP has revealed the presence of two CEs running in the hydrophobic tunnel and two plugged-in phospholipids (PLs) near the concave surface. Other than previous animal models that rule out the PL transfer by CETP and PLs in providing the structural stability, the functional importance of bound phospholipids in CETP is not fully explored. Here, we employ a series of molecular dynamics (MD) simulations, steered molecular dynamics (SMD) simulations, and free energy calculations to unravel the effect of PLs on the functionality of the protein. Our results suggest that PLs play an important role in the transfer of neutral lipids by transforming the unfavorable bent conformation of CEs into a favorable linear conformation to facilitate the smooth transfer. The results also suggest that the making and breaking interactions of the hydrophobic tunnel residues with CEs with a combined effort from PLs are responsible for the transfer of CEs. Further, the findings demonstrate that the N-PL has a more pronounced effort on CE transfer than C-PL but efforts from both PLs are essential in the transfer. Thus, we propose that the functionally important PLs can be considered with potential research interest in targeting cardiovascular diseases.

Structural analysis and molecular dynamics simulation studies of HIV-1 antisense protein predict its potential role in HIV replication and pathogenesis.

The functional significance of the HIV-1 Antisense Protein (ASP) has been a paradox since its discovery. The expression of this protein in HIV-1-infected cells and its involvement in autophagy, transcriptional regulation, and viral latency have sporadically been reported in various studies. Yet, the definite role of this protein in HIV-1 infection remains unclear. Deciphering the 3D structure of HIV-1 ASP would throw light on its potential role in HIV lifecycle and host-virus interaction. Hence, using extensive molecular modeling and dynamics simulation for 200 ns, we predicted the plausible 3D-structures of ASP from two reference strains of HIV-1 namely, Indie-C1 (subtype-C) and NL4-3 (subtype-B) so as to derive its functional implication through structural domain analysis. In spite of sequence and structural differences in subtype B and C ASP, both structures appear to share common domains like the Von Willebrand Factor Domain-A (VWFA), Integrin subunit alpha-X (ITGSX), and ETV6-Transcriptional repressor, thereby reiterating the potential role of HIV-1 ASP in transcriptional repression and autophagy, as reported in earlier studies. Gromos-based cluster analysis of the centroid structures also reassured the accuracy of the prediction. This is the first study to elucidate a highly plausible structure for HIV-1 ASP which could serve as a feeder for further experimental validation studies.