Life depends to large extent on biochemical processes happening in deeply buried active sites. Penetration of protein tunnels is an ubiquitous process, perhaps the most studied example is oxygen diffusion in heme globular proteins. Molecular dynamics (MD) simulations may help to elucidate ligand transport paths inside protein matrices and a sequence of events accompanying in this traffic. Unfortunately, plain MD is not practical to this end – hopping across energy barriers is often a rare event and extremely long simulation times are required to get decent statistics. In the talk we will present an overview of the recent progress in the simulations using accelerated enhanced MD methods, in particular those that help to calculate ligand diffusion paths. For example, Locally Enhanced Sampling brings better understanding of cytoglobin , neuroglobin  and nitrile hydratase  activities. Recently, we have suggested a few new memetic algorithms, based on the immune system activity and ant colonies behavior . The new approach is based on Steered MD Simulations and Random Expulsion Method by R. Wade at al. , but preliminary calculations show that our approach outperforms the existing methods. Examples of ligands’ navigation through cytochrome P450cam, nitrile hydrates, and GPCR muscarinic receptor M2 will be presented. We hope, that our new computational scheme will help others to grasp better dynamical phenomena tuned by proteins’ architectures functionally refined through the ages of the Evolution.