| There is a direct connection between the structure of biomacromolecules and their properties and functions. Unfortunately, biological systems frequently impose experimental limitations such that it becomes impossible to obtain more than low- to medium-resolution structural data. We studied three systems to illustrate how experiments can be coupled to molecular dynamics (MD) simulations in order to interpret data and gain insights about biological processes.; We used MD to run simulations of trimeric, hexameric, nonameric, and dodecameric segments of aqueous pullulan using implicit (AMBER* & GB/SA) and explicit (CHARMM & TIP3P) solvents. We generated small-angle X-ray scattering data to compare to results obtained experimentally and through a rotational isomeric states (RIS) model. Our results show that: GB/SA is unsuitable for such simulations; the previous success of the RIS model is based on unrealistic conformational sampling; and the Guinier approximation tends to underestimate radii of gyration.; We combined MD simulations (CHARMM & TIP3P) to electron paramagnetic resonance data to understand how the C2 domain of cytosolic phospholipase A2 is able to dock to palmitoyl-oleyl-phosphatidylcholine (POPC) bilayers. We find that the diverse interactions offered by the thermally disordered, chemically heterogeneous interfacial zones of PC bilayers allow local lipid remodeling to produce a nearly perfect match to the shape and polarity of the C2 domain. The result is a cup-like docking site with hydrophobic bottom and hydrophilic rim. Moreover, we have invalidated the hypothesis that calcium-lipid interactions keep the protein embedded.; We generated two sets of hydrophobic alpha-helical peptides, KKPKL nKPKK (Kn) and GGPGLnGPGG (Gn), with n = 6, 8, 10, 12, and 20, to investigate how short transmembraneous peptides manage to violate the hydrophobic matching hypothesis and insert into lipid bilayers. We found that all peptides remained inserted during the MD simulations, an observation confirmed experimentally. These systems are stable because: the bilayer caves in around the segments in order to minimize hydrophobic mismatching; and the solvent penetrates deep inside the bilayer to optimize hydrogen-bonding with the capping residues and with parts of the helices.; Overall, these simulations provided molecular pictures that furthered our understanding of physico-chemical processes involved in biomacromolecular systems of physiological interest. |
