Biomolecular Recognition: The Current Challenge - Dynamic Force Spectroscopy and Biomolecular Recognition - page 39

L-selectin behavior and the existence of two conformations, with a possible effect of
forces on transition between these two states [120]. In a later paper [121], the authors
suggested a more precise mechanism.
Dissecting the kinetics of molecular interactions. The interaction between acetyl-
cholinesterase and tetramethylammonium (TMA), a molecule resembling the bulki-
est part of acetylcholine, was studied with molecular dynamics. The authors con-
cluded that local conformational fluctuations were required to allow the ligand pas-
sage [25]. More recently, molecular dynamics was used to investigate the mech-
anisms of interactions between tyrosine kinases and a monoclonal antibody [3].
The authors concluded that binding preferences were determined by conformational
selection.
Predicting molecular interactions. A major goal of molecular simulation is to pre-
dict molecular interactions. As already mentioned, molecular simulations have been
used for years to try and predict molecular associations [49] [100] in addition to other
knowledge-based approaches [41] [107]. As indicated above, it would be most useful
to be able to predict molecular interactions and the present state of the art is reviewed
in CAPRI rounds [70]. Successes go on being reported in present day literature
[49] [81].
1.6 CONCLUSION
Biomolecule recognition is a process of outstanding biological importance that has
been studied for decades with standard physical-chemical methods and concepts,
based on the determination of affinity constants and kinetic association and dissoci-
ation rates. Results were interpreted within the framework of thermodynamics, sta-
tistical physics, and physical chemistry as elaborated nearly a century ago. More
recently, the experimental dissection of molecular interactions at the single bond
level, increasing availability of structural data with nearly Angstr om resolution, and
development of simulation methods with a power matching protein complexity made
it conceivable to describe molecular interactions with much improved accuracy, with
a deeper understanding of the force sensitivity and transition between a multitude
of substates. In parallel, the progress of our understanding of all the complexity of
biological systems is an incentive to use this new kind of knowledge to achieve a
better understanding of cell function. It is hoped that the development of DFS will
be a substantial factor of progress along this line.
REFERENCES
1. Alberts, B., A. Johnson, J. Lewis, M. Raff, K. Roberts, and P. Walter. 2008. Molecular
Biology of the Cell 5th edition, New York: Garland.
2. Alder, B. J., and T. E. Wainwright. 1959. Studies in molecular dynamics. I. General
methods. J. Chem. Phys. 31:459-466.