Proteins exist in myriad of conformations in solution, but due to their enormous degrees of freedom, it is impossible to computationally enumerate their entire conformational space. It is important to incorporate the most populated receptor states in structure based drug design methods to better mimic experimental reality. Numerous methods have been devised to incorporate the plasticity of proteins but either they are computationally very expensive or they are unable to obtain a converged partition function within a limited structural ensemble. We have developed a method, (Movable Type with Receptor Flexibility (MTRec-flex)) which enumerates conformational states based on the side chain and backbone flexibility on a free energy surface. This Lego based approach treats the molecular structure at an atom pair level and generates all the conformations of an atom using position and distances with respect to different reference atoms. Every selected distance is associated with a pair potential value chosen from a prebuilt atom-pairwise energy database indexed with atom pair types at discrete distances. Similar to 3-D printing, each block of generated atom-pairs is combined to yield a molecular geometry. Energy of a conformation is obtained by summing up all the bonded and non-bonded energy components for each atom pair obtained from the energy database. Subsequently, the relative free energies are obtained using the Movable Type (MT) free energy method[1]. This method with its parallel conformation generation ability is less computationally intensive and it provides us with energies with the associated structures. The resultant conformational states can then be used in subsequent docking and scoring exercises. 1. Zheng, Z., M.N. Ucisik, and K.M. Merz, Jr., The Movable Type Method Applied to Protein-Ligand Binding. J Chem Theory Comput, 2013. 9(12): p. 5526-5538.

MTRec-flex: A novel method for incorporating flexibility in the receptor’s binding pocket

251st National Meeting (2016)

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