The presentation of antigenic peptide-MHCII complexes (pMHCIIs) for surveillance by T cells is a well-known immunological concept in vertebrates, yet the conformational dynamics of antigen exchange ...remain elusive. By combining NMR-detected H/D exchange with Markov modelling analysis of an aggregate of milliseconds of adaptive molecular dynamics simulations, we reveal that a stable pMHCII spontaneously samples intermediate conformations that are both relevant for peptide exchange and consistent with X-ray crystallography.
Immobilization of enzymes into different support materials has been widely studied as means to control their activity and stability. Here we will consider lipid liquid crystalline phases as enzyme ...carriers, as they have been demonstrated to have a high potential in a range of applications such as drug delivery, protein encapsulation or crystallization thanks to the wide range of self-assembly structures they can form, which have cavities of nano-scale dimensions. Furthermore, such structures have also been observed in a range of living organisms. Although, reverse cubic or hexagonal lipid aqueous phase can be used to entrap smaller biomolecules, it is still challenging to encapsulate bioactive macromolecules, such as proteins. Here, we will present a novel lipid system able to form highly swollen sponge phases (L3), with aqueous pores up to 13 nm of diameter. We will show that this structure is preserved even in excess aqueous solution, where they form sponge-like nanoparticles (L3 NPs) in which two enzymes of different sizes, Aspartic protease and beta-galactosidase (34 KDa and 460 KDa, respectively), could be included. To reveal the nature of the interaction between the enzymes and the lipid matrix, we studied the adsorption of both proteins on the lipid layers formed by the L3 NPs. The results will be discussed in terms of the ability of these nanoparticles to encapsulate and release of the proteins in the lipid matrix.
Understanding of intracellular polymerization of sickle hemoglobin (HbS) and subsequent interaction with the membrane of a red blood cell (RBC) is important to predict the altered morphologies and ...mechanical properties of sickle RBCs in sickle cell anemia. However, modeling the integrated processes of HbS nucleation, polymerization, HbS fiber interaction, and subsequent distortion of RBCs is challenging as they occur at multispatial scales, ranging from nanometers to micrometers. To make progress toward simulating the integrated processes, we propose a hybrid HbS fiber model, which couples fine-grained and coarse-grained HbS fiber models through a mesoscopic adaptive resolution scheme (MARS). To this end, we apply a microscopic model to capture the dynamic process of polymerization of HbS fibers, while maintaining the mechanical properties of polymerized HbS fibers by the mesoscopic model, thus providing a means of bridging the subcellular and cellular phenomena in sickle cell disease. At the subcellular level, this model can simulate HbS polymerization with preexisting HbS nuclei. At the cellular level, if combined with RBC models, the generated HbS fibers could be applied to study the morphologies and membrane stiffening of sickle RBCs. One important feature of the MARS is that it can be easily employed in other particle-based multiscale simulations where a dynamic coarse-graining and force-blending method is required. As demonstrations, we first apply the hybrid HbS fiber model to simulate the interactions of two growing fibers and find that their final configurations depend on the orientation and interaction distance between two fibers, in good agreement with experimental observations. We also model the formation of fiber bundles and domains so that we explore the mechanism that causes fiber branching.
We present OpenRBC, a coarse-grained molecular dynamics code, which is capable of performing an unprecedented in silico experiment—simulating an entire mammal red blood cell lipid bilayer and ...cytoskeleton as modeled by multiple millions of mesoscopic particles—using a single shared memory commodity workstation. To achieve this, we invented an adaptive spatial-searching algorithm to accelerate the computation of short-range pairwise interactions in an extremely sparse three-dimensional space. The algorithm is based on a Voronoi partitioning of the point cloud of coarse-grained particles, and is continuously updated over the course of the simulation. The algorithm enables the construction of the key spatial searching data structure in our code, i.e., a lattice-free cell list, with a time and space cost linearly proportional to the number of particles in the system. The position and the shape of the cells also adapt automatically to the local density and curvature. The code implements OpenMP parallelization and scales to hundreds of hardware threads. It outperforms a legacy simulator by almost an order of magnitude in time-to-solution and >40 times in problem size, thus providing, to our knowledge, a new platform for probing the biomechanics of red blood cells.
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