Computational profiling of pore properties of outer membrane proteins

Computational profiling of pore properties of outer membrane protein

Computational analysis of BACE1-ligand complex crystal structures and linear discriminant analysis for identification of BACE1 inhibitors with anti P-glycoprotein binding property

More than 100 years of research on Alzheimer’s disease didn’t yield a potential cure for this dreadful disease. Poor Blood Brain Barrier (BBB) permeability and P-glycoprotein binding of BACE1 inhibitors are the major causes for the failure of these molecules during clinical trials. The design of BACE1 inhibitors with a balance of sufficient affinity to the binding site and little or no interaction with P-glycoproteins is indispensable. Identification and understanding of protein–ligand interactions are essential for ligand optimization process. Structure-based drug design (SBDD) efforts led to a steady accumulation of BACE1-ligand crystal complexes in the PDB. This study focuses on analyses of 153 BACE1-ligand complexes for the direct contacts (hydrogen bonds and weak interactions) observed between protein and ligand and indirect contacts (water-mediated hydrogen bonds), observed in BACE1-ligand complex crystal structures. Intraligand hydrogen bonds were analyzed, with focus on ligand P-glycoprotein efflux. The interactions are dissected specific to subsites in the active site and discussed. The observed protein-ligand and intraligand interactions were used to develop the linear discriminant model for the identification of BACE1 inhibitors with less or no P-glycoprotein binding property. Excellent statistical results and model’s ability to correctly predict a new data-set with an accuracy of 92% is achieved. The results are retrospectively analyzed to give input for the design of potential BACE1 inhibitors.</p

Modeling the Closed and Open State Conformations of the GABA_A Ion Channel - Plausible Structural Insights for Channel Gating

Recent disclosure of high resolution crystal structures of <i>Gloeobacter violaceus</i> (GLIC) in open state and <i>Erwinia chrysanthemii</i> (ELIC) in closed state provides newer avenues to advance our knowledge and understanding of the physiologically and pharmacologically important ionotropic GABA_A ion channel. The present modeling study envisions understanding the complex molecular transitions involved in ionic conductance, which were not evident in earlier disclosed homology models. In particular, emphasis was put on understanding the structural basis of gating, gating transition from the closed to the open state on an atomic scale. Homology modeling of two different physiological states of GABA_A was carried out using their respective templates. The ability of induced fit docking in breaking the critical inter residue salt bridge (Glu155β₂ and Arg207β₂) upon endogenous GABA docking reflects the perceived side chain rearrangements that occur at the orthosteric site and consolidate the quality of the model. Biophysical calculations like electrostatic mapping, pore radius calculation, ion solvation profile, and normal-mode analysis (NMA) were undertaken to address pertinent questions like the following: How the change in state of the ion channel alters the electrostatic environment across the lumen; How accessible is the Cl^– ion in the open state and closed state; What structural changes regulate channel gating. A “Twist to Turn” global motion evinced at the quaternary level accompanied by tilting and rotation of the M2 helices along the membrane normal rationalizes the structural transition involved in gating. This perceived global motion hints toward a conserved gating mechanism among pLGIC. To paraphrase, this modeling study proves to be a reliable framework for understanding the structure function relationship of the hitherto unresolved GABA_A ion channel. The modeled structures presented herein not only reveal the structurally distinct conformational states of the GABA_A ion channel but also explain the biophysical difference between the respective states

Modeling the Closed and Open State Conformations of the GABA_A Ion Channel - Plausible Structural Insights for Channel Gating

Recent disclosure of high resolution crystal structures of <i>Gloeobacter violaceus</i> (GLIC) in open state and <i>Erwinia chrysanthemii</i> (ELIC) in closed state provides newer avenues to advance our knowledge and understanding of the physiologically and pharmacologically important ionotropic GABA_A ion channel. The present modeling study envisions understanding the complex molecular transitions involved in ionic conductance, which were not evident in earlier disclosed homology models. In particular, emphasis was put on understanding the structural basis of gating, gating transition from the closed to the open state on an atomic scale. Homology modeling of two different physiological states of GABA_A was carried out using their respective templates. The ability of induced fit docking in breaking the critical inter residue salt bridge (Glu155β₂ and Arg207β₂) upon endogenous GABA docking reflects the perceived side chain rearrangements that occur at the orthosteric site and consolidate the quality of the model. Biophysical calculations like electrostatic mapping, pore radius calculation, ion solvation profile, and normal-mode analysis (NMA) were undertaken to address pertinent questions like the following: How the change in state of the ion channel alters the electrostatic environment across the lumen; How accessible is the Cl^– ion in the open state and closed state; What structural changes regulate channel gating. A “Twist to Turn” global motion evinced at the quaternary level accompanied by tilting and rotation of the M2 helices along the membrane normal rationalizes the structural transition involved in gating. This perceived global motion hints toward a conserved gating mechanism among pLGIC. To paraphrase, this modeling study proves to be a reliable framework for understanding the structure function relationship of the hitherto unresolved GABA_A ion channel. The modeled structures presented herein not only reveal the structurally distinct conformational states of the GABA_A ion channel but also explain the biophysical difference between the respective states

Modeling the Closed and Open State Conformations of the GABA_A Ion Channel - Plausible Structural Insights for Channel Gating

Recent disclosure of high resolution crystal structures of <i>Gloeobacter violaceus</i> (GLIC) in open state and <i>Erwinia chrysanthemii</i> (ELIC) in closed state provides newer avenues to advance our knowledge and understanding of the physiologically and pharmacologically important ionotropic GABA_A ion channel. The present modeling study envisions understanding the complex molecular transitions involved in ionic conductance, which were not evident in earlier disclosed homology models. In particular, emphasis was put on understanding the structural basis of gating, gating transition from the closed to the open state on an atomic scale. Homology modeling of two different physiological states of GABA_A was carried out using their respective templates. The ability of induced fit docking in breaking the critical inter residue salt bridge (Glu155β₂ and Arg207β₂) upon endogenous GABA docking reflects the perceived side chain rearrangements that occur at the orthosteric site and consolidate the quality of the model. Biophysical calculations like electrostatic mapping, pore radius calculation, ion solvation profile, and normal-mode analysis (NMA) were undertaken to address pertinent questions like the following: How the change in state of the ion channel alters the electrostatic environment across the lumen; How accessible is the Cl^– ion in the open state and closed state; What structural changes regulate channel gating. A “Twist to Turn” global motion evinced at the quaternary level accompanied by tilting and rotation of the M2 helices along the membrane normal rationalizes the structural transition involved in gating. This perceived global motion hints toward a conserved gating mechanism among pLGIC. To paraphrase, this modeling study proves to be a reliable framework for understanding the structure function relationship of the hitherto unresolved GABA_A ion channel. The modeled structures presented herein not only reveal the structurally distinct conformational states of the GABA_A ion channel but also explain the biophysical difference between the respective states