Structural Elucidation of Macromolecules
Pp. 30-91 (62)
Ana Luisa Carvalho, Teresa Santos-Silva, Maria Joao Romao, Eurico J. Cabrita and Filipa Marcelo
While the structures of many proteins and nucleic acids are known and
available in the Protein Data Bank, the folding and active sites of many fundamental
macromolecules are yet to be elucidated. However, structure determination is only a
small part of the story; to fully understand the diversity of functions that
macromolecules have in living systems, interactions have also to be considered. Most
drugs interact with macromolecular targets and the understanding of ligandmacromolecular
recognition is fundamental in medicinal chemistry either from a purely
structural viewpoint or by considering other important effects such as: ligand and
binding site dynamics, distortion energies, solvent interactions and entropy. This
chapter provides a comprehensive view on the several methods that are nowadays used
to obtain structural information about macromolecules and their interactions with small
ligands. The methods presented encompass different levels of characterization, either
coarse information about the 3D shape or detailed structural data at the atomic level.
Furthermore, relevance is given to the structural characterization of ligand binding
events, either from the ligand or from the macromolecule viewpoint. Some
experimental details behind X-ray crystallography, Nuclear Magnetic Resonance
(NMR) and Small Angle X-ray Scattering (SAXS) are described, with examples and
applications. An overview on Cryo-Electron Microscopy (CryoEM) is also presented.
These are common state-of-the-art tools that truly complement each other and should
be used in an integrative way.
Cryo-EM, Drug design, Macromolecular structure, NMR, Proteinligand
interactions, SAXS, X-ray crystallography.
UCIBIO-REQUIMTE, Departamento de Química, Faculdade de Ciencias e Tecnologia, Universidade Nova de Lisboa, 2829-516, Caparica, Portugal.