TRAJELIX: A computational tool for the geometric characterization of protein helices during molecular dynamics simulations Mihaly Mezei a, * & Marta Filizola b a Department of Physiology and Biophysics, Mount Sinai School of Medicine, NYU, One Gustave L. Levy Place, Box 1218, New York, NY, 10029, USA; b Department of Physiology & Biophysics, Weill Medical College of Cornell University, 1200 York Ave, New York, NY 10021, USA Received 29 July 2005; accepted 9 February 2006 Ó Springer 2006 Key words: helix geometry, a-helical proteins, membrane proteins, MD, SIMULAID Summary We have developed a computer program with the necessary mathematical formalism for the geometric characterization of distorted conformations of alpha-helices proteins, such as those that can potentially be sampled during typical molecular dynamics simulations. This formalism has been incorporated into TRAJELIX, a new module within the SIMULAID framework (http://inka.mssm.edu/mezei/simulaid/) that is capable of monitoring distortions of alpha-helices in terms of their displacement, global and local tilting, rotation around their axes, compression/extension, winding/unwinding, and bending. Accurate evaluation of these global and local structural properties of the helix can help study possible intramolecular and intermolecular changes in the helix packing of alpha-helical membrane proteins, as shown here in an application to the interacting helical domains of rhodopsin dimers. Quantification of the dynamic structural behavior of alpha-helical membrane proteins is critical for our understanding of signal transduction, and may enable structure-based design of more specific and efficient drugs. Introduction Alpha (a)-helices are prominent structural ele- ments of proteins. In particular, alpha-helical membrane proteins constitute about 20–25% of the proteome, and about half of the potential pharmaceutical targets. Since the most prominent structural characteristic of these proteins is their bundles of transmembrane (TM) a-helices, de- tailed knowledge of the dynamic structural behav- ior of each helix in the bundle upon activation is considered vital in structure-based drug design. The usefulness of studying changes in the geomet- ric characteristics of transmembrane helical bun- dles is illustrated by the observation that helix distortions in membrane proteins may play impor- tant functional roles (e.g., see [1]). During typical all-atom molecular dynamics (MD) simulations the protein helices undergo not only changes in their overall appearance in relation to the rest of the bundle, but also continual distortions of their local structural features, as often found in globular proteins [2, 3]. These distortions make the deter- mination of global helix properties a complex task. For helices with an ideal geometry the atoms defining the helix unequivocally define the axis as well. In contrast, for distorted helices the definition of helical axis is not straightforward, as demon- strated by the number of algorithms available for helix axis determination. A comparative evalua- tion of these algorithms can be found in [4]. Characterization of changes in the geometric *To whom correspondence should be addressed. Phone: +212-241-2186; Fax: +212-860-3369 E-mail: mezei@inka.mssm.edu Journal of Computer-Aided Molecular Design (2006) 20: 97–107 DOI 10.1007/s10822-006-9039-1