Nanoparticles in biological systems encounter lipid-bilayer membranes as barriers. They interact with plasma membranes, membranous organelles, such as the endoplasmic reticulum and the Golgi apparatus, the nucleus, and intracellular and extracellular vesicles, such as autophagosomes, lysosomes, and exosomes. Extracellular vesicles have recently attracted particular attention, as they are involved in the transmission of biological signals and as regulators for biological processes. For example, exosomes, small vesicles containing proteins, mRNA, and miRNA, that are released by cells into the extracellular environment, have been suggested to participate in tumor metastasis. Furthermore, vesicles can be applied as targeted-drug-delivery systems. We systematically characterize wrapping of spherical nanoparticles that enter and exit vesicles, depending on particle size, vesicle size, vesicle reduced volume, and membrane spontaneous curvature. We predict the complex wrapping behavior, in particular for large particle-to-vesicle size ratios, where the shape changes of the free membrane contribute significantly to the deformation energy and where nanoparticle wrapping transitions and vesicle shape transitions are coupled. Partial-wrapped membrane-bound particles impose boundary conditions on the membrane that stabilise oblates and stomatocytes for particle entry, and prolates and stomatocytes for particle exit. Our results suggest that nanoparticles may stimulate autophagocytic engulfment, which would facilitate transport of the nanoparticles into lysosomes and would lead to subsequent degradation of nanoparticle-attached proteins.

Antibody-antigen specific recognition is essential in autoimmunity. In this study, antibody SPE7 binding to protein antigens and to hapten molecules were carefully analyzed in order to gain insight into their binding mechanisms. X-ray crystal structures show that SPE7 can adopt at least four different conformations, as in the two observed free isomers (Ab(1) and Ab(2)) and the two observed bound conformers (Ab(3) and Ab(4)). Multidimensional scaling analysis reveals that antibody SPE7 may obey a global conformational selection mechanism upon its binding to an antigen. The conformations of key residue at the binding site (Trp93L) further reveals that bound isomer Ab(3) may come from free isomer Ab(2), and bound isomer Ab(4) from free isomer Ab(1). The average root-mean-square deviation (RMSD) values between the bound isomers and the corresponding free isomers and Kolmogorov-Smimov P test analysis indicate that the antibody may also follow a local induced fit mechanism at the binding interface. Quantitative analysis indicates that the magnitude of the local induced fit interaction at the binding site is more pronounced than that of the global conformational selection interaction. These conclusions are further supported by high-temperature unbinding kinetics analysis. The computational methods proposed here can also be used to study the specific recognitions between other antibody and antigen systems.

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Amyloid fibrils play causal roles in the pathogenesis of amyloid-related degenerative diseases such as Alzheimer's disease, type II diabetes mellitus, and the prion-related transmissible spongiform encephalopathies. The mechanism of fibril formation and protein aggregation is still hotly debated and remains an important open question in order to develop therapeutic method of these diseases. However, traditional molecular biological and crystallographic experiments could hardly observe atomic details and aggregation process. Molecular dynamics (MD) simulations could provide explanations for experimental results and detailed pathway of protein aggregation. In this review, we focus on the applications of MD simulations on several amyloidogenic protein systems. Furthermore, MD simulations could help us to understand the mechanism of amyloid aggregation and how to design the inhibitors.

In vivo, high protein and ion concentrations determine the preferred volumes of cells, organelles, and vesicles. Deformations of their lipid-bilayer membranes by nanoparticle wrapping reduce the interior volumes available to solutes and thus induce large osmotic pressure differences. Osmotic concentration can therefore be an important control parameter for wrapping of nanoparticles. We employ a curvatureelasticity model of the membrane and contact interaction with spherical particles to study their wrapping at initially spherical vesicles. Although the continuous particle-binding transition is independent of the presence of solutes, the discontinuous envelopment transition shifts to higher adhesion strengths and the corresponding energy barrier increases with increasing osmotic concentration. High osmotic concentrations stabilize partial-wrapped, membrane-bound states for both, particle attachment to the inside and the outside. In this regime, wrapping of particles controls membrane tension, with power-law dependencies on osmotic concentration and adhesion strength. For high adhesion strengths, particle wrapping can lead to the opening of mechanosensitive channels in cell membranes and to lysis. Membrane tension-induced stabilization of partial-wrapped states as well as wrapping-induced lysis play important roles not only for desired mechano-bacteriocidal effects of engineered nanomaterials but may also determine viral burst sizes of bacteria and control endocytosis for mammalian cells.

Amyloid fibrils are found in many fatal neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, type II diabetes, and prion disease. The VEALYL short peptide from insulin has been confirmed to aggregate amyloid-like fibrils. However, the aggregation mechanism of amyloid fibril is poorly understood. Here, we utilized molecular dynamics simulation to analyse the stability of VEALYL hexamer. The statistical results indicate that hydrophobic residues play key roles in stabilizing VEALYL hexamer. Single point and two linkage mutants confirmed that Val1, Leu4, and Tyr5 of VEALYL are key residues. The consistency of the results for the VEALYL oligomer suggests that the intermediate states might be trimer (3-0) and pentamer(3-2). These results can help us to obtain an insight into the aggregation mechanism of amyloid fibril. These methods can be used to study the stability of amyloid fibril from other short peptides.

The transactivation domain (TAD) of tumor suppressor p53 can bind with the nuclear coactivator binding domain (NCBD) of cyclic-AMP response element binding protein (CBP) and activate transcription. NMR experiments demonstrate that both apo-NCBD and TAD are intrinsic disordered and bound NCBD/TAD undergoes a transition to well folded. The recognition mechanism between intrinsic disordered proteins is still hotly debated. Molecular dynamics (MD) simulations in explicit solvent are used to study the recognition mechanism between intrinsic disordered TAD and NCBD. The average RMSD values between bound and corresponding apo states and Kolmogorov-Smirnov P test analysis indicate that TAD and NCBD may follow an induced fit mechanism. Quantitative analysis indicates there is also a global conformational selection. In summary, the recognition of TAD and NCBD might obey a local induced fit and global conformational selection. These conclusions are further supported by high-temperature unbinding kinetics and room temperature landscape analysis. These methods can be used to study the recognition mechanism of other intrinsic disordered proteins.

The transactivation domain (TAD) of tumor suppressor p53 can bind with the nuclear coactivator binding domain (NCBD) of cyclic-AMP response element binding protein (CBP) and activate transcription. NMR experiments demonstrate that both apo-NCBD and TAD are intrinsic disordered and bound NCBD/TAD undergoes a transition to well folded. The recognition mechanism between intrinsic disordered proteins is still hotly debated. Molecular dynamics (MD) simulations in explicit solvent are used to study the recognition mechanism between intrinsic disordered TAD and NCBD. The average RMSD values between bound and corresponding apo states and Kolmogorov-Smirnov P test analysis indicate that TAD and NCBD may follow an induced fit mechanism. Quantitative analysis indicates there is also a global conformational selection. In summary, the recognition of TAD and NCBD might obey a local induced fit and global conformational selection. These conclusions are further supported by high-temperature unbinding kinetics and room temperature landscape analysis. These methods can be used to study the recognition mechanism of other intrinsic disordered proteins.