Analysis of basic clustering algorithms for numerical estimation of statistical averages in biomolecules.

In statistical mechanics, the equilibrium properties of a physical system of particles can be calculated as the statistical average over accessible microstates of the system. In general, these calculations are computationally intractable since they involve summations over an exponentially large number of microstates. Clustering algorithms are one of the methods used to numerically approximate these sums. The most basic clustering algorithms first sub-divide the system into a set of smaller subsets (clusters). Then, interactions between particles within each cluster are treated exactly, while all interactions between different clusters are ignored. These smaller clusters have far fewer microstates, making the summation over these microstates, tractable. These algorithms have been previously used for biomolecular computations, but remain relatively unexplored in this context. Presented here, is a theoretical analysis of the error and computational complexity for the two most basic clustering algorithms that were previously applied in the context of biomolecular electrostatics. We derive a tight, computationally inexpensive, error bound for the equilibrium state of a particle computed via these clustering algorithms. For some practical applications, it is the root mean square error, which can be significantly lower than the error bound, that may be more important. We how that there is a strong empirical relationship between error bound and root mean square error, suggesting that the error bound could be used as a computationally inexpensive metric for predicting the accuracy of clustering algorithms for practical applications. An example of error analysis for such an application-computation of average charge of ionizable amino-acids in proteins-is given, demonstrating that the clustering algorithm can be accurate enough for practical purposes.