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===Satisfaction of spatial restraints===
The most common current homology modeling method takes its inspiration from calculations required to construct a three-dimensional structure from data generated by NMR spectroscopy. One or more target-template alignments are used to construct a set of geometrical criteria that are then converted to probability density functions for each restraint. Restraints applied to the main protein internal coordinates - protein backbone distances and dihedral angles - serve as the basis for a global optimization procedure that originally used conjugate gradient energy minimization to iteratively refine the positions of all heavy atoms in the protein.

This method had been dramatically expanded to apply specifically to loop modeling, which can be extremely difficult due to the high flexibility of loops in proteins in aqueous solution. A more recent expansion applies the spatial-restraint model to electron density maps derived from cryoelectron microscopy studies, which provide low-resolution information that is not usually itself sufficient to generate atomic-resolution structural models. To address the problem of inaccuracies in initial target-template sequence alignment, an iterative procedure has also been introduced to refine the alignment on the basis of the initial structural fit. The most commonly user software in spatial restraint-based modeling is MODELLER and a database called ModBase has been established for reliable models generated with it.