A historical perspective on the application of molecular dynamics (MD) to biological macromolecules is presented. Recent developments combining state-of-the-art force fields with continuum solvation calculations have allowed us to reach the fourth era of MD applications in which one can often derive both accurate structure and accurate relative free energies from molecular dynamics trajectories. We illustrate such applications on nucleic acid duplexes, RNA hairpins, protein folding trajectories, and proteinligand, protein-protein, and protein-nucleic acid interactions.

Computer modeling has been developed and widely applied in studying molecules of biological interest. The force field is the cornerstone of computer simulations, and many force fields have been developed and successfully applied in these simulations. Two interesting areas are (a) studying enzyme catalytic mechanisms using a combination of quantum mechanics and molecular mechanics, and (b) studying macromolecular dynamics and interactions using molecular dynamics (MD) and free energy (FE) calculation methods. Enzyme catalysis involves forming and breaking of covalent bonds and requires the use of quantum mechanics. Noncovalent interactions appear ubiquitously in biology, but here we confine ourselves to review only noncovalent interactions between protein and protein, protein and ligand, and protein and nucleic acids.

The cost burden is high for systemic fungal infections. Additional attention should be given to the 55% with fungal disease and other comorbid diagnoses.