First Principles Metadynamics Simulations of Rare Events
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14th of December at 13.40. MDBF G077

First Principles Metadynamics Simulations of ‘Rare Events’ in Biological Systems
Saron Catak
Center for Molecular Modeling, Ghent University, Technologiepark 903,
B-9052 Zwijnaarde, Belgium,

The current challenge of molecular simulations is the description of reaction coordinates that characterize processes of biological interest. To this end, determination of free-energy changes along reaction coordinates constitutes an even greater challenge. The most reliable way to obtain this data requires long molecular dynamics (MD) simulations, however, most chemical reactions are rare events and have barriers higher than a few kcal/mol; this renders these simulations beyond the scope of current computational means. Advanced sampling techniques have been designed to overcome the problems in modeling rare events. Among these techniques, metadynamics [1] is one of the most recently developed methodologies used in the field of biomolecular simulations and is a very powerful tool to study chemical reactions that involve multiple possible pathways and many different intermediary minima. This approach is becoming increasingly popular in the investigation of solvent catalyzed reactions where the solvent plays a critical role in the reaction mechanism.
Herein, the deamidation of asparagines residues in proteins, a reaction catalyzed by the solvent environment [2], will be investigated with first principles metadynamics simulations in order to elucidate the reaction mechanism. Asparagine residues are known to spontaneously –yet non-enzymatically– deamidate to form aspartatic acid residues under physiological conditions, causing time-dependent changes in charge and conformation of proteins, hence, limiting their lifetime. This has led to the ‘molecular clocks’ hypothesis [3], which suggests that deamidation is a biological molecular timing mechanism that could be set to any desired time interval by genetic control of the primary, secondary, and tertiary structure surrounding the amide. Deamidation occurs over a wide range of biologically relevant time intervals; this suggests that different mechanisms may be operative. Metadynamics simulations reveal the true nature of the free energy surface and the most plausible routes to deamidation of asparagines.
[1] L. Alessandro, L. G. Francesco, Reports on Progress in Physics 71, 126601 (2008)
[2] N. E. Robinson and A. B. Robinson, Proc. Natl. Acad. Sci. USA, 98, 944 (2001) [3] S. Catak, G. Monard, V. Aviyente and M. F. Ruiz-López, J. Phys. Chem. A, 113, 1111 (2009)