Multiscale simulations of protein landscapes: Using coarse-grained models as reference potentials to full explicit models

Evaluating the free‐energy landscape of proteins and the corresponding functional aspects presents a major challenge for computer simulation approaches. This challenge is due to the complexity of the landscape and the enormous computer time needed for converging simulations. The use of simplified coarse‐grained (CG) folding models offers an effective way of sampling the landscape but such a treatment, however, may not give the correct description of the effect of the actual protein residues. A general way around this problem that has been put forward in our early work (Fan et al., Theor Chem Acc 1999;103:77–80) uses the CG model as a reference potential for free‐energy calculations of different properties of the explicit model. This method is refined and extended here, focusing on improving the electrostatic treatment and on demonstrating key applications. These applications include: evaluation of changes of folding energy upon mutations, calculations of transition‐states binding free energies (which are crucial for rational enzyme design), evaluations of catalytic landscape, and evaluations of the time‐dependent responses to pH changes. Furthermore, the general potential of our approach in overcoming major challenges in studies of structure function correlation in proteins is discussed. Proteins 2010. © 2009 Wiley‐Liss, Inc.