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\subsection{Shape Queries}  Similarity of molecular shape is a common method of structure-based virtual screening \cite{Nicholls_2010}. Pharmit uses the Volumetric Aligned Molecular Shapes (VAMS) \cite{vams} method of shape search, which uses inclusive and exclusive shape constraints to identify matching molecular shapes. Inclusive constraints are specified using the shape of the provided ligand or by manually specified inclusion spheres. Inclusive constraints specify a minimum bound on the desired molecular shape; matching compounds will overlap these  constraints. Exclusive constraints are specified using the shape of the provided receptor or by manually specified exclusion spheres. Exclusive constraints are used to limit the desired molecular shape; matching compounds are prohibited from overlapping these constraints. Both constraints are represented using voxelized volumes, as shown in Figure~\ref{shapefig}, and can be adjusted by growing or shrinking the constraint volume.  \cite{matchpack}\cite{vams}  Users have the option of using shape as an additional constraint on the similarity search. The ligand's surface or a set of user-defined spheres may be used as an inclusive constraint, the receptor's surface or a set of user-defined spheres may be used as an exclusive constraint, or both inclusive and exclusive shapes may be used. Multiple spheres may be defined for both inclusive and exclusive search by choosing the "Spheres" option in the dropdown menu and pressing "Add". This will display a menu allowing the user to set the position and size of the sphere. Pressing "Add" again will enable the user to continue adding spheres. The shape constraint is applied differently depending on whether it is used to search the database prior to pharmacophore filtering or to filter results returned by a pharmacophore search. In the former case, a shape search returns molecules in the search database that contain the entire included shape and do not overlap any part of the excluded shape. In the latter case, the results of the pharmacophore search are filtered by shape to ensure that at least one heavy atom falls within the inclusive shape and no heavy atom centers fall within any exclusive shape. In either case, the results of the initial search are aligned to that search for the secondary filtering - thus for a given molecule a pose may exist that allows it to meet the secondary filter, but it will not be returned if the aligned pose resulting from the initial search does not meet those constraints. Our recommendation is that users define both inclusive and exclusive shape constraints using the ligand and receptor surfaces and use them as secondary filtering on the results of a pharmacophore search. The order of application of pharmacophore and shape constraints can be swapped using the second button from the top of the left sidebar, which switches between "Pharmacophore Search → Shape Filter" and "Shape Search → Pharmacophore Filter".  \subsection{Visualization}  Next, it will center the features and use a set of default visualization options to display the provided structures, including the electrostatic surface of the receptor. If the user is dissatisfied with the default visualization scheme, they may scroll down to the "Visualization" menu in the left sidebar and toggle the options as desired. In particular, if the electrostatic surface of the receptor is obscuring the pharmacophore features, receptor surface opacity may be reduced and at the lowest setting becomes entirely transparent. In the graphical display window, the left mouse button may be used to rotate the scene and the right mouse button or center wheel may be used to zoom. Clicking on spheres - both pharmacophore spheres and shape constraint spheres - toggles between a solid and wire display. In order to maximize the viewable graphical display area, the sidebar may be hidden by pressing the left-pointing arrowhead at the top right of the sidebar.