Molecular Dynamics Studies on the Lipid Transfer Protein - STARD11

Abstract

The STARD11 protein plays a crucial role in the transport of ceramide from the endoplasmic reticulum (ER) to the Golgi apparatus. Ceramide is a lipid molecule that is essential for several cellular processes such as cell growth, differentiation, and programmed cell death (apoptosis). The STARD11 protein has a hydrophobic cavity that can bind to one lipid at a time. However, to accommodate for the ceramide molecule, structural rearrangements of the protein are required. Molecular dynamics studies have shed a light on the conformational changes that occur in the STARD11 protein during ceramide binding. In particular, the movement of the alfa4-helix and/or the omega1-loop, and omega4-loop regions appear to be highly dynamic and play a critical role in the binding process. To further understand the structural basis of ceramide binding by STARD11, we conducted a series of molecular dynamics simulations. Our study involved 15 different systems, including wild-type STARD11 with and without ceramide binding, as well as double and single mutation of specific amino acids. By analysing the simulations, we were able to gain insight into the molecular interactions between STARD11 and ceramide, as well as identify key regions that are essential for the binding process. Our study has revealed interesting finding regarding the structural stability of the wild type holo and apo proteins. Specifically, we observed that the wild type holo protein exhibits a higher degree of structural stability compared to the wild type apo protein. Moreover, our study examined the single mutation on the holo and apo proteins, and found that single mutation had greater impact on the structure of the apo protein compared to the holo form. These findings suggests that the presence of a bound lipid can enhance the stability to the protein, possibly by restricting its flexibility. The MSMs analysis allowed for calculating probabilities and study transition between certain states, and we found that there was a significant likelihood that the W473A/W562A apo protein exhibits a larger opening in the omega1- omega4-loop, and alfa4-helix regions compared to the WT apo protein. These observations are important for understanding the relationship between protein structure and functions, as well as the effect of ligand binding on the protein stability.