Solution based measurement of Solvent-Accessible Surface Area of macromolecules The Solvent-Accessible Surface Area (SASA) is a valuable metric for looking at protein folding and protein-protein interactions. However, this measurement is typically done by calculating the SASA from a solved (and generally static) structure.

Chemical probes like diazirine and hydroxyl radicals show some bias regarding where they tend to bind. I'm realizing while I'm writing this question that NMR is a perfectly valid method to determine a solution based structure and then calculate the SASA. Similar strategies has also been used to examine structured RNAs. I'm curious about the variety of these methods and how accurate they are.
As you noted, the solvent-accessible surface area is a geometric concept, and as such is most easily calculated using computational geometry tools from a given molecular (or crystalline) structure. However you obtain this atomistic structure (X-ray, neutrons, molecular simulation, NMR, …) is of course of significant importance to the resulting area, but the calculation method will be the same.

There are, however, a few studies which have attempted to link the solvent-accessible surface area to directly measurable properties, and in particular to spectroscopic properties. A quick search of the literature reveals three examples:


Amide H/2H Exchange MALDI-TOF Mass Spectrometry
UV Raman directly on the exposed residues
Using diazirine as a probe