Metal ions are found in the core of several phenomena such as biomolecular recognition and protein (un)folding and are directly involved in a number of diseases. Some of these important processes usually take place on the micro- to millisecond time scales. Low-energy states relevant for these processes may be separated by high-energy barriers, which are rarely crossed over the course of molecular dynamics simulations. Therefore, methods that enhance conformational sampling are needed to elucidate the role of metal ions in these important biological phenomena at a reasonable computational cost. Accelerated molecular dynamics (aMD) enhances sampling in a relatively simple way (a priori knowledge of the underlying free energy landscape is not needed).[1,2] Recently, we explored the performance of aMD to predict the detailed mechanisms of protein folding. The folding and the free energy landscape of fast-folding proteins, including Trp-cage, villin headpiece and WW domain, was simulated with aMD. This allowed us to identify distinct conformational states (e.g. unfolded and intermediate) other than the native structure and the protein folding energy barriers.[3] Here, we combine aMD simulations with electronic structure calculations for the metal parametrization[4] to efficiently explore the conformational space of metal-directed protein folding and biomolecular recognition processes. In particular, we analyze the role of Cu(II) metal ion to determine the secondary structure of a synthetic switchable peptide (20 aa) that alternates the conformation from an alpha-helix to a beta-sheet depending on the presence of Cu(II). This model peptide has been proposed as a model for neurodegenerative diseases. [1] P.R. Markwick, J.A. McCammon, Phys. Chem. Chem. Phys., 13, 20053 (2011) [2] F. Feixas, S. Lindert, W. Sinko, J. A. McCammon, Biophys. Chem., 186, 31 (2014) [3] Y. Miao, F. Feixas, C. Eun, J. A. McCammon, J. Comp. Chem,. 36, 1536 (2015) [4] A.P.T. Carvalho, M. Swart, J. Chem. Inf. Model. 54, 613 (2014)

Accelerating metal-directed protein folding and molecular recognition with enhanced sampling techniques

251st National Meeting (2016)

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