Conformational Flooding

`Conformational Flooding' is a novel method to study and to predict conformational motions in macromolecular systems (especially in proteins) on a microsecond time scale. Such motions typically occur as conformational (structural) transitions between distinct conformational substates [13,1]. Such motions may be localized, as for example ring flips, or collective in nature and quite complex, like T-R-transitions, or the gating of ion channels. With few exceptions, conformational motions are slow on the MD accessible time scale with mean transition times ranging from nanoseconds to hours. For a review on conformational transitions, see, e.g., Ref. [14]. For theoretical studies, see Refs. [11,18,36,15,25].

`Conformational Flooding' aims at these rare events, which, at present, cannot be predicted with traditional molecular dynamics (MD) simulations. Given an initial conformation of the system, the method identifies one or more product states, which may be separated from the initial state by free energy barriers that are large on the scale of thermal energy. It also provides approximate reaction paths, which can be used to determine barrier heights or reaction rates with the usual techniques like umbrella sampling [38]. The method employs an artificial potential that destabilizes the initial conformation and, thereby, lowers free energy barriers of structural transitions. As a result, transitions are accelerated by several orders of magnitude and thus may be observed in MD-simulations.

Conformational flooding has a variety of applications in several fields, e.g., as a tool for protein structure determination or conformational search, to check the stability of protein models, to predict functional motions, or to improve estimates of thermodynamic quantities such as free energies and entropies for proteins, polymers or glasses.

A typical `flooding-simulation' involves several steps.

(1)

Prepare the system and carry out conventional MD-simulations.

(2)

After spending many CPU-hours you realize that the conformational motion of interest does not occur within available simulation time; you decide to use `conformational flooding'.

(3)

Decide which atoms the destabilizing forces shall be acted upon (e.g., C-alpha atoms).

(4)

Use an equilibrated trajectory of an MD-run (as long as possible, e.g., several 100 ps) to generate an approximate description of the initial conformational substate by `mkflood'. This description is referred to as a `flooding matrix'.

(5)

Estimate an appropriate flooding strength.

(6)

Switch on the destabilizing flooding potential (derived from the flooding matrix) and run a `flooding' simulation.

(7)

Observe the value of the flooding potential as it evolves during the flooding simulation. A sudden jump to small values indicates the conformational transition you look for.

(8)

If no conformational transition is observed within available computer time, the flooding strength was probably chosen too small. Go to (5), maybe to (3).

(9)

Analyze the observed transition, look for further transitions starting with the new structure, or write a paper.

These steps are explained in detail below.