Hydrogen Bond Switching

By Jocelyne Vreede

Hydrogen bonds play an important role in stabilizing (meta-)stable states in protein folding. Hence, they can potentially be used as a way to bias towards these states in molecular simulation methods. We have developed two types of hydrogen bond biasing potentials, repulsive biasing potentials that disrupt weak hydrogen bonds, and attractive biasing potentials that enable faster hydrogen bond formation between likely hydrogen bond candidates. These potentials depend on the positions of the acceptor, the donor and the hydrogen atom.

Folding and unfolding a short polypeptide using the hydrogen bond switching technique

We applied the hydrogen bond biasing potentials in a replica-exchange scheme, called hydrogen bond switching (HS). In such a scheme, several identical molecular dynamics simulations, called replicas, run simultaneously with gradually increasing strength of the biasing potentials. There is also one replica in which no additional biasing potential is present, which is called the neutral replica. At fixed time intervals, attempts are made to swap biasing potentials between two replicas, according to a Metropolis criterion. If the swap is successful, the two replicas will exchange their biasing potentials. The conformations that contribute to the neutral replica represent the conformational sampling of the system in equilibrium. Compared to conventional MD, this sampling is significantly faster and more efficient.

Another popular method to speed up sampling of protein conformational change is tenperature replica-exchange, in which replicas run at different temperatures. To compare the performance of the HS to a temperature replica-exchange, we performed HS and temperature replica-exchange simulations of a beta-heptapeptide in methanol. Both methods sample the conformational space to a similar extent. As the HS simulation required only five replicas, while the REMD simulation required 20 replicas, the HS method is significantly more efficient.


  • J. Vreede, M.G. Wolf, S.W. de Leeuw, and P.G. Bolhuis
    J. Phys. Chem. B (2009),