Modelling conformational changes using metadynamics in essential coordinates


V. Spiwok1, P. Lipovová1, B. Králová1


1Department of Biochemistry and Microbiology, Institute of Chemical Technology Prague, Technická 3, Prague 6, 166 28, Czech Republic


Accurate modelling of conformational changes in bio-macromolecules is fundamental for understanding the role of protein motions in catalysis, allosteric effect, induced fit, molecular motors, folding, unfolding, misfolding and many other processes. However, conformational motions are often not accessible by means of standard molecular dynamics simulation because of time-consuming nature of this method. Moreover, standard molecular dynamics simulation does not provide any quantitative information about free energy changes. The recently introduced method of metadynamics [1] makes possible to explore a free energy surface of a molecular system in the space of collective variables. These collective variables are parameters that determine the progress along the modelled conformational (or other chemical) change. Parameters such as distances between two atoms or dihedral angles are often used as collective variables. The choice of these collective variables is usually intuitive and a matter of experience. In modelling conformational changes it is often difficult to find suitable collective variables. Here we present metadynamics in space of essential coordinates obtained by essential dynamics analysis [2] of molecular dynamics trajectory. Essential dynamics (principle component analysis) allows tracing major collective motions in the dynamics of a bio-macromolecule. The results of metadynamics in space of essential coordinates applied to the model molecule (alanine dipeptide, Ace-Ala-Nme) are presented. These results demonstrate that a combination of these two methods (essential dynamics and metadynamics) has great potential in modelling of conformational changes.


1.     A. Laio, M. Parrinello, Proc. Natl. Acad. Sci. U.S.A. 99, (2002), 12562.

2.     A. Amadei, A. B. Linssen, H. J. Berendsen, Proteins. 17, (1993), 412.



This work was supported by the Academy of Sciences of the Czech Republic (GAAV KJB 500500512) and the Ministry of Education, Youth and Sports (MSM 6046137305).