The cellular membrane constitutes one of the most fundamental compartments of a living cell, where key processes such as selective transport of material and exchange of information between the cell and its environment are mediated by proteins that are closely associated with the membrane. The heterogeneity of lipid composition of biological membranes and the effect of lipid molecules on the structure, dynamics, and function of membrane proteins are now widely recognized. Characterization of these functionally important lipid-protein interactions with experimental techniques is however still prohibitively challenging. Molecular dynamics (MD) simulations offer a powerful complementary approach with sufficient temporal and spatial resolutions to gain atomic-level structural information and energetics on lipid-protein interactions. In this review, we aim to provide a broad survey of MD simulations focusing on exploring lipidprotein interactions and characterizing lipid-modulated protein structure and dynamics that have been successful in providing novel insight into the mechanism of membrane protein function.

Roughly half of the drug overdose-related deaths in the United States are related to synthetic opioids represented by fentanyl which is a potent agonist of mu-opioid receptor (mOR). In recent years, X-ray crystal structures of mOR in complex with morphine derivatives have been determined; however, structural basis of mOR activation by fentanyl-like opioids remains lacking. Exploiting the X-ray structure of BU72-bound mOR and several molecular simulation techniques, we elucidated the detailed binding mechanism of fentanyl. Surprisingly, in addition to the salt-bridge binding mode common to morphinan opiates, fentanyl can move deeper and form a stable hydrogen bond with the conserved His2976.52, which has been suggested to modulate mOR’s ligand affinity and pH dependence by previous mutagenesis experiments. Intriguingly, this secondary binding mode is only accessible when His2976.52 adopts a neutral HID tautomer. Alternative binding modes may represent a general mechanism in G protein-coupled receptor-ligand recognition.

Carboxysomes are closed polyhedral cellular microcompartments that increase the efficiency of carbon fixation in autotrophic bacteria. Carboxysome shells consist of small proteins that form hexameric units with semipermeable central pores containing binding sites for anions. This feature is thought to selectively allow access to RuBisCO enzymes inside the carboxysome by HCO (the dominant form of CO in the aqueous solution at pH 7.4) but not O, which leads to a nonproductive reaction. To test this hypothesis, here we use molecular dynamics simulations to characterize the energetics and permeability of CO, O, and HCO through the central pores of two different shell proteins, namely, CsoS1A of α-carboxysome and CcmK4 of β-carboxysome shells. We find that the central pores are in fact selectively permeable to anions such as HCO, as predicted by the model.

The steroid hormone 1␣,25(OH) 2 -vitamin D 3 (1,25D) 2 (see Fig. 1) and the nuclear vitamin D receptor (VDR) forms a complex that modulates the transcription of genes containing a VDR element. This process is termed a genomic response and involves 1,25D binding to the VDR, formation of a heterodimer with retinoid X receptor, and recruitment of nuclear co-activators (NCoAs) and the basal transcription machinery (1).The VDR is a member of the nuclear hormone superfamily of transcription factors, all of which share similar domain partitioning, ligand binding domain (LBD) tertiary fold and localization of their ligand binding pocket (LBP). The current inducedfit model describing nuclear receptor (NR) activation (i.e. the mouse-trap model) is founded on the comparison of apo-and holo-NR x-ray crystal structures. The mouse trap model posits that closure of the NR activation helix (i.e. helix-12) is induced by ligand binding to an opened-like helix-12 apo-NR conformer. The closed helix-12 conformation completes the activation function II domain (AF2), which serves as the high affinity binding site for recruitment of various NCoAs (1-4) (Fig. 2). Thus, the steric blockage of NR helix-12 closure is the basis for the design of traditional NR genomic antagonists (5-9).