Markov state models (MSMs) are very popular and have a rigorous basis in principle, but applying them in practice must be done with great caution. There is no guarantee the results will be reliable for complex systems of typical interest unless there is an enormous amount of data and significant expertise and validation goes into the MSM building. And even if those conditions are in place, certain observables likely will be biased.

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#### CategoryFirst-passage times

If the two-state system is the hydrogen atom, the three-state system is the hydrogen molecule. We have plenty more to learn about the three-state system. Mastering this material will really boost your confidence with non-equilibrium systems. Of course, we already studied the two-state system *when it was out of equilibrium:* remember the relaxation time ? But that was relaxation to equilibrium. Relaxation to a non-equilibrium steady state (NESS) is more interesting.

This is yet another one of those things where, after reading this, you’re supposed to say, “Oh, that’s obvious.” And I admit it is kind of obvious … after you think about it for a few minutes! So spend those few minutes now to learn one more cool thing about non-equilibrium trajectory physics.

In non-equilibrium calculations of transition processes, we often wish to estimate a rate constant, which can be quantified as the inverse of the mean first-passage time (MFPT). That is, one way to define a rate constant is just reciprocal of the average time it takes for a transition. The Hill relation tells us that probability flow per second into a target state of interest (state “B”, defined by us) is *exactly* the inverse MFPT … so long as we measure that flow in the A-to-B steady state based on initializing trajectories outside state B according to some distribution (state “A”, defined by us) and we remove trajectories reaching state B and re-initialize them in A according to our chosen distribution.

**Basic strategies, timescales, and limitations**

**Basic strategies, timescales, and limitations**

Key biomolecular events – such as conformational changes, folding, and binding – that are challenging to study using straightforward simulation may be amenable to study using “path sampling” methods. But there are a few things you should think about before getting started on path sampling. *There are fairly generic features and limitations* that govern all the path sampling methods I’m aware of.

*Path sampling* refers to a large family of methods that, rather than having the goal of generating an ensemble of system configurations, attempt to generate an ensemble of dynamical *trajectories*. Here we are talking about trajectory ensembles that are precisely defined in statistical mechanics. As we have noted in another post, there are different kinds of trajectory ensembles – most importantly, the equilibrium ensemble, non-equilibrium steady states, and the initialized ensemble which will relax to steady state. Typically, one wants to generate trajectories exhibiting events of interest – e.g., binding, folding, conformational change.

The trajectory ensemble is everything you’ve always wanted, and more. Really, it is. Trajectory ensembles unlock fundamental ideas in statistical mechanics, including connections between equilibrium and non-equilibrium phenomena. Simple sketches of these objects immediately yield important equations without a lot of math. Give me the trajectory-ensemble pictures over fancy formalism any day. It’s harder to make a mistake with a picture than a complicated equation.

A trajectory, speaking roughly, is a time-ordered sequence of system configurations. Those configurations could be coordinates of atoms in a single molecule, the coordinates of many molecules, or whatever objects you like. We assume the sequence was generated by some real physical process, so typically we’re considering finite-temperature dynamics (which are intrinsically stochastic due to “unknowable” collisions with the thermal bath). The ‘time-ordered sequence’ of configurations really reflects continuous dynamics, so that the time-spacing between configurations is vanishingly small, but that won’t be important for this discussion.

The “Hill relation” is a key result for anyone interested in calculating rates from trajectories of any kind, whether molecular simulations or otherwise. I am not aware of any really clear explanation, including Hill’s original presentation. Hopefully this go-around will make sense.

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