Geometric measures of large biomolecules: surface, volume, and pockets

Geometry plays a major role in our attempts to understand the activity of large molecules. For example, surface area and volume are used to quantify the interactions between these molecules and the water surrounding them in implicit solvent models. In addition, the detection of pockets serves as a starting point for predictive studies of biomolecule-ligand interactions. The alpha shape theory provides an exact and robust method for computing these geometric measures. Several implementations of this theory are currently available. We show however that these implementations fail on very large macromolecular systems. We show that these difficulties are not theoretical; rather, they are related to the architecture of current computers that rely on the use of cache memory to speed up calculation. By rewriting the algorithms that implement the different steps of the alpha shape theory such that we enforce locality, we show that we can remediate these cache problems; the corresponding code, UnionBall has an apparent O(n) behavior over a large range of values of n (up to tens of millions), where n is the number of atoms. As an example, it takes 136 sec with UnionBall to compute the contribution of each atom to the surface area and volume of a viral capsid with more than five million atoms on a commodity PC. UnionBall includes functions for computing analytically the surface area and volume of the intersection of two, three and four spheres that are fully detailed in an appendix. UnionBall is available as an OpenSource software.