Review: recent advances and current challenges in scanning probe microscopy of biomolecular surfaces and interfaces.

The introduction of scanning probe microscopy (SPM) techniques revolutionized the field of condensed matter science by allowing researchers to probe the structure and composition of materials on an atomic scale. Although these methods have been used to make molecular- and atomic-scale measurements on biological systems with some success, the biophysical sciences remain on the cusp of a breakthrough with SPM technologies similar in magnitude to that experienced by fields related to solid-state surfaces and interfaces. Numerous challenges arise when attempting to connect biological molecules that are often delicate, dynamic, and complex with the experimental requirements of SPM techniques. However, there are a growing number of studies in which SPM has been successfully used to achieve subnanometer resolution measurements in biological systems where carefully designed and prepared samples have been paired with appropriate SPM techniques. We review significant recent innovations in applying SPM techniques to biological molecules, and highlight challenges that face researchers attempting to gain atomic- and molecular-level information of complex biomolecular structures.