Structural Quality and MD Simulations of Homology Models of Major Facilitator Superfamily (MFS) Transporter Proteins

Abstract

Title: Structural Quality and MD Simulations of Homology Models of Major Facilitator Superfamily (MFS) Transporter ProteinsThe MFS is a large group of transporter proteins that catalyze uniport; solute:cation symport; and/or solute:cation or solute:solute antiport. Currently, relatively few experimental structures are known for these membrane transport proteins. Homology modeling enables us to extrapolate from X-ray structures of (bacterial) MFS proteins. However, quality assessment of homology models is crucial, especially given the relatively low resolution of some of the template structures. Furthermore, although structurally conserved, the MFS transporters do not share high sequence identity (i.e. less than 30% identity is observed). In this work, homology models of MFS were constructed based on crystal structures of lactose permease (LacY, PDB ID 1PV7), GlpT (PDB ID 1PW4) and the multidrug transporter EmrD (PDB ID 2GFP). These MFS model structures, as well as MFS crystal structures, were subjected to atomistic and coarse grained (CG) MD simulations. Quality assessments and measures of conformational “stability” of the simulated structures were compared for homology models and X-ray structures. It was concluded that local stereochemical quality of MFS protein structures does not predict conformational “stability” of the protein in MD simulations. An extensive stereochemical analysis based on known membrane protein crystal structures and corresponding MD simulation data was used to assess the MFS model structures. It was shown that MD stereochemical profiles can be used to distinguish between models constructed based on high quality template structures, models constructed based on a low quality template structures, and ‘decoys’(i.e. models constructed based on a incorrectly chosen templates).