Biomolecular Recognition: The Current Challenge - Dynamic Force Spectroscopy and Biomolecular Recognition - page 2

1.5.2.2 Dynamics of Ligand-Receptor Interaction ........................ 32
1.5.2.3 Mechanisms Influencing the Specificity of Biomolecule
Interaction........................................................................... 34
1.5.3 Information Yielded by Computer Simulation................................... 35
1.5.3.1 Limitations and Technical Advances.................................. 37
1.5.3.2 New Information on Molecular Association May Be
Provided by Computer Simulations ................................... 38
1.6 Conclusion ...................................................................................................... 39
References................................................................................................................ 39
1.1 INTRODUCTION
Life relies on myriads of interactions between the molecular components of liv-
ing systems. Proteins are a remarkable example in view of their diversity (the very
name of proteins stems from Proteus, a Greek god known for his capacity to change
shape). Several decades ago, the author of a well-known treatise on proteins [45]
wrote that “... the biological function of proteins almost invariably depends on their
direct physical interaction with other molecules.” More recently, systematic use of
powerful techniques such as yeast double hybrid or mass spectrometry was the basis
for a large-scale attempt to build exhaustive databases of protein interactions, the so-
called interactome [16]. Over 250,000 interactions between about 22,000 proteins
were recorded in the Unified Interactome Database in the year 2008 [30].
Until recently, it seemed that the conventional concepts and methods used to study
chemical equilibria provided a suitable framework to deal with biomolecular recog-
nition. As was reckoned two decades ago [195], the concepts of specificity and affin-
ity had seemed sufficient to deal with biological phenomena for many years, and
only conventional kinetic constants had to be added to explain some recent find-
ings. However, a number of reports supported the importance of forces in biological
interactions [28] [94] and theoretical models of cell functions such as adhesion have
included mechanical parameters [13] [127]. This was an incentive to devise exper-
imental methods allowing us to study the response of biomolecules to forces with
high temporal and spatial resolution up to the single molecule level. Simultaneously,
continuous progress in molecular dynamics allowed computer scientists to report on
simulations of the response of biomolecules to external forces [83] [93] [160], thus
allowing deeper interpretation of experimental results [71] [167]. These advances
were also facilitated by the tremendous increase of structural data on biomolecules,
based on X-ray crystallography and nuclear magnetic resonance (NMR), and the use
of genetic engineering techniques to relate structural and functional data, as exempli-
fied by alanine scanning that consists of systematically replacing amino acids with
alanin in protein-protein interaction areas to obtain a direct estimate of their con-
tribution to binding energy [47]. The development of dynamic force spectroscopy
(DFS) is a remarkable example of an innovative approach stemming for a number of
different advances and yielding a new kind of information that might shed new light
on important and unresolved issues.