Protein structural biology came a long way since the determination of the first three-dimensional structure of myoglobin about six decades ago. Across this period, X-ray crystallography was the most important experimental method for gaining atomic-resolution insight into protein structures. However, as the role of dynamics gained importance in the function of proteins, the limitations of X-ray crystallography in not being able to capture dynamics came to the forefront. Computational methods proved to be immensely successful in understanding protein dynamics in solution, and they continue to improve in terms of both the scale and the types of systems that can be studied. In this review, we briefly discuss the limitations of X-ray crystallography in studying protein dynamics, and then provide an overview of different computational methods that are instrumental in understanding the dynamics of proteins and biomacromolecular complexes.

The separation of lipid mixtures into thermodynamically stable phase-separated domains is dependent on lipid composition, temperature, and system size. Using molecular dynamics simulations, the line tension between thermodynamically stable lipid domains formed from ternary mixtures of di-C16:0 PC:di-C18:2 PC:cholesterol at 40:40:20 mol. % ratio was investigated via two theoretical approaches. The line tension was found to be 3.1 ± 0.2 pN by capillary wave theory and 4.7 ± 3.7 pN by pressure tensor anisotropy approaches for coarse-grained models based on the Martini force field. Using an all-atom model of the lipid membrane based on the CHARMM36 force field, the line tension was found to be 3.6 ± 0.9 pN using capillary wave theory and 1.8 ± 2.2 pN using pressure anisotropy approaches. The discrepancy between estimates of the line tension based on capillary wave theory and pressure tensor anisotropy methods is discussed. Inclusion of protein in Martini membrane lipid mixtures was found to reduce the line tension by 25%–35% as calculated by the capillary wave theory approach. To further understand and predict the behavior of proteins in phase-separated membranes, we have formulated an analytical Flory-Huggins model and parameterized it against the simulation results. Taken together these results suggest a general role for proteins in reducing the thermodynamic cost associated with domain formation in lipid mixtures and quantifies the thermodynamic driving force promoting the association of proteins to domain interfaces.

Molecular self‐diffusion coefficients underlie various kinetic properties of the liquids involved in chemistry, physics, and pharmaceutics. In this study, 547 self‐diffusion coefficients are calculated based on all‐atom molecular dynamics (MD) simulations of 152 diverse pure liquids at various temperatures employing the OPLS4 force field. The calculated coefficients are compared with experimental data (424 extracted from the literature and 123 newly measured by pulsed‐field gradient nuclear magnetic resonance). The calculations well agree with the experimental values. The determination coefficient and root mean square error between the observed and calculated logarithmic self‐diffusion coefficients of the 547 entries are 0.931 and 0.213, respectively, demonstrating that the MD calculation can be an excellent industrial tool for predicting, for example, molecular transportation in liquids such as the diffusion of active ingredients in biological and pharmaceutical liquids. The self‐diffusion coefficients collected in this study are compiled into a database for broad researches including artificial intelligence calculations.

Polymer electrolyte membranes, for example, the Nafion™ membranes, used in the fuel cells are responsible for separating reactive gas molecules as well as for the efficient exchange of protons. Although control of the permeation of the gases is important to enhance the fuel cell performance, the mechanism by which hydrogen and oxygen molecules permeate through the membranes remains unclear. To clarify the mechanism, we investigated the three-dimensional free-energy landscape of hydrogen and oxygen molecules in Nafion membranes with various water contents focusing on relevant diffusion paths. Low-free-energy paths are found mainly in the polymer phase and the interfacial region between the polymer and water phases. Thus, the path of the transportation may be attributed to the polymer phase and interfacial phases. However, the free-energy value in the aqueous phase is only slightly higher (∼1–2 k_BT) than that in the other two phases, which indicates that a secondary contribution from the aqueous phase is expected. The free-energy landscape in the polymer and interfacial phases was found rugged, while it is comparatively flat in the water phase. We also found that an increase in water content brings about a smoother free-energy landscape in the polymer and interfacial phases. The decreased ruggedness may facilitate the gas diffusivity. These observations help understand the molecular mechanism of the gas diffusion in the membranes.