Impact of water models on structure and dynamics of ligand-transport tunnels in enzymes derived from molecular dynamics simulations

Abstract

ABSTRACTProtein hydration plays a vital role in many biological functions. Molecular simulations are frequently used to study the effect of hydration on proteins at the atomic level. However, the accuracy of these simulations has often been highly sensitive to the water model used, perhaps best known in the case of intrinsically disordered proteins. In the present study, we have investigated to what extent the choice of a water model alters the behavior of complex networks of transport tunnels, which are critical for function of many enzymes with buried active sites. By performing all-atom molecular dynamics simulations of the haloalkane dehalogenase LinBWT and its two variants, LinB32 and LinB86, with synthetically engineered tunnel networks in TIP3P and OPC water models, we investigated their effects on the overall tunnel topology, properties of the main tunnels such as their conformation, residue composition, and duration of their open states. Our data showed that while all three proteins exhibited similar conformational behavior in both water models, they differed in the duration of openings of their main tunnels and, in limited cases, also in the properties of their auxiliary tunnels. Interestingly, the results indicate that the stability of the open tunnels is sensitive to the water model, rendering the generally more accurate OPC water model a preferred choice here, particularly when the kinetics of the ligand transport process is under question. However, since the TIP3P model can provide comparable inference on the overall topology of the networks of primary tunnels and their geometry, it may still be a relevant option when computational resources are limited.