Simulating the molecular processes of living matter - what is missing from current models*

Modeling and simulations of biological systems help to understand how biological functions occur, how molecules that generate the functions are activated, and how the function of these molecules can be controlled. However, the challenge for simulation models is that very often they do not correspond to conditions that prevail in living matter. Although biological processes occur under equilibrium conditions, they are often simulated in equilibrium. Although proteins are often enzymatically glycosylated, this is typically not considered in simulation models. The function of proteins is very sensitive to the protonation states of their amino acids, but these are very difficult to account for, for example, in the vicinity of cell membranes, where the electrostatic environment is exceptionally heterogeneous and poorly defined. These and many other similar situations illustrate the challenges that need to be addressed to allow simulation of biomolecular functions under realistic conditions matching in vivo experiments. In this work, we discuss the significance of these challenges as well as the preliminary methodological work that has been conducted.