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

Abstract

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.

pH‐sensitive residues in the p19 RNA silencing suppressor protein from carnation Italian ringspot virus affect siRNA binding stability

“…Often referred to as constant pH MD (CPHMD) simulations, the titration coordinate is typically implemented in either a discrete manner [31][32][33][34][35][36][37][38][39][40][41][42][43] where protonation states are modified with an MC step at some regular MD interval or using a continuous function [44][45][46] that describes the protonation state via the k dynamics method developed by Brooks and coworkers. [47][48][49] Recent studies have shown that CPHMD is a reliable and robust method that is capable of predicting pK a values in a variety of biomolecular systems.…”

Electrostatic origin of the mechanochemical rotary mechanism and the catalytic dwell of F1-ATPase

“…18 and 20) is also unlikely to yield the correct free energy trend. Thus we used in this work our CG model that focuses on consistent description of the electrostatic energy of the system (21). We assumed that because this CG model has been very effective in reproducing protein folding energies and other properties (22,23), it should provide an effective strategy for capturing the energetics underlying the function of molecular motors.…”

Realistic simulations of the coupling between the protomotive force and the mechanical rotation of the F 0 -ATPase

“…We have embedded the system in a rectangular membrane where both the protein and the lipid were represented by our CG model. The protein residues were represented with explicit backbone atoms and the side chains were represented with a single united atom (21), while the membrane was represented through a grid of effective atoms with a 3 Å spacing. The membrane block has a width of about 30 Å and the central Asp residues of the c-ring were placed almost at the middle of the membrane.…”

“…It is important to emphasize that previous attempts to model the asymmetry were not based on a validated experience in modeling charges in protein interiors or on familiarity with the corresponding issue. This is exactly the issue that has been extensively studied by us (26) and has led to the electrostatic features of our CG model (21). At present, the CG is far more reliable in assessing pK a and electrostatic free energies in nonpolar regions of protein/membrane systems than the standard FEP calculations [e.g., of the type used in ref.…”

“…The power of CG models in studying other macromolecular systems is further illustrated in recent works (19,20). Thus we used our CG model with specialized electrostatic treatment (21) and explored the molecular origin of the rotational motion of F 0 . Remarkably, it is found that the rotation is due to asymmetry in the energetics of the proton path rather than just the asymmetry of the interaction between the Asp and Arg ions.…”