The increased interest in studying membrane proteins has led to the development of new membrane mimics such as bicelles and nanodiscs. However, only limited knowledge is available of how these membrane mimics are affected by embedded proteins and how well they mimic a lipid bilayer. Herein, we present molecular dynamics simulations to elucidate structural and dynamic properties of small bicelles and compare them to a large alignable bicelle, a small nanodisc, and a lipid bilayer. Properties such as lipid packing and properties related to embedding both an α-helical peptide and a transmembrane protein are investigated. The small bicelles are found to be very dynamic and mainly assume a prolate shape substantiating that small bicelles cannot be regarded as well-defined disclike structures. However, addition of a peptide results in an increased tendency to form disc-shaped bicelles. The small bicelles and the nanodiscs show increased peptide solvation and difference in peptide orientation compared to embedding in a bilayer. The large bicelle imitated a bilayer well with respect to both curvature and peptide solvation, although peripheral binding of short tailed lipids to the embedded proteins is observed, which could hinder ligand binding or multimer formation.

Low-barrier hydrogen bond (LBHB) involvement in enzyme catalysis is examined by analysis of experimental nuclear and electron densities of a model compound for the catalytic triad in serine proteases (shown schematically), which is based on a cocrystal of betaine, imidazole, and picric acid. The three short, strong N-H⋅⋅⋅O hydrogen bonds in the structure have varying degrees of covalent bonding contributions suggesting a gradual transition to the LBHB situation.

Graphical Abstract

Prion diseases are associated with the misfolding of the prion protein (PrP) from its normal cellular form (PrPC) to its infectious scrapie form (PrPSc). Posttranslational modifications of PrP in vivo can play an important role in modulating the process of misfolding. To gain more insight into the effects of posttranslational modifications on PrP structure and dynamics and to test the hypothesis that such modifications can interact with the protein, we have performed molecular dynamics simulations of diglycosylated human PrPC bound to a lipid bilayer via a glycophosphatidylinositol anchor. Multiple simulations were performed at three different pH ranges to explore pH effects on structure and dynamics. In contrast to simulations of protein-only PrPC, no large effects were observed upon lowering the pH of the system. The protein tilted toward the membrane surface in all of the simulations and the putative PrPSc oligomerization sites became inaccessible, thereby offering a possible protective mechanism against PrPSc-induced misfolding of PrPC.

A characteristic property of intrinsically disordered and unfolded proteins is their high molecular flexibility, which enables the exploration of a large conformational space. We present neutron scattering experiments on the structure and dynamics of the intrinsically disordered myelin basic protein (MBP) and the chemically denatured bovine serum albumin (BSA) in solution. Small-angle neutron scattering (SANS) experiments allowed us to gain information of structural aspects of MBP and denatured BSA as response to denaturant conditions. Using neutron spin-echo spectroscopy (NSE), we were able to investigate collective motions of the protein chain up to several hundred nanoseconds on the nanometre length-scale. NSE results showed a high flexibility of the unfolded proteins. Internal motions of the intrinsically disordered MBP and denatured BSA were described using normal mode analysis and concepts derived from polymer theory. The contribution of residue-solvent friction was accounted for using the Zimm model including internal friction. Motions of MBP are well described by collective normal modes, while dynamics of denatured BSA shows polymer-like properties. Disulphide bonds forming loops of amino acids of the peptide backbone have a major impact on internal dynamics of denatured BSA that can be interpreted with a reduced set of Zimm modes.