Geometrical Conversion of the EGFR Extracellular Domain by Adiabatic Mapping Combining Normal Mode Analysis of the Elastic Network Model and Energy Optimization.

The activation of epidermal growth factor receptor (EGFR) involves the geometrical conversion of the extracellular domain (ECD) from the tethered to the extended forms with the dynamic rearrangement of the relative positions of four subdomains (SDs); however, this conversion process has not yet been thoroughly understood. We compare the two different forms of the X-ray crystal structures of ECD and simulate the ECD conversion process using adiabatic mapping that combines normal mode analysis of the elastic network model (ENM-NMA) and energy optimization. A comparison of the crystal structures reveals the rigidity of the intradomain geometry of the SD-I and -III backbone regardless of the form. The forward mapping from the tethered to the extended forms retains the intradomain geometry of the SD-I and -III backbone and reveals the trends to rearrange the relative positions of SD-I and -III and to dissociate the C-terminal tail of SD-IV from the hairpin loop in SD-II. The reverse mapping from the extended to the tethered forms complements the promotion of ECD conversion in the presence of epidermal growth factor (EGF).

Molecular recognition study on the binding of calcium to calbindin D9k based on 3D reference interaction site model theory.

Ca(2+)-binding proteins are widely distributed throughout cells and play various important roles. Calbindin D9k is a member of the EF-hand Ca(2+)-binding protein family. In this study, we examined the binding of Ca(2+) to calbindin D9k in terms of the free energy of solvation, as obtained by 3D reference interaction site model theory, which describes the statistical mechanics of liquids. We also investigated the main structural biological factor using spatial decomposition analysis in which the solvation free energy values are decomposed into the residue. We found some characteristic residues that contribute to stabilization of the holo-structure (Ca(2+)-binding structure). These results indicated that, in the holo-structure, these residues are newly exposed to solvent. Subsequently, the gain in solvation free energy, involving a conformational change and exposure to solvent, forms the driving force for binding of the Ca(2+) ion to the EF-hand.

A New Approach for Investigating the Molecular Recognition of Protein: Toward Structure-Based Drug Design Based on the 3D-RISM Theory.

A new approach to investigate a molecular recognition process of protein is presented based on the three-dimensional reference interaction site model (3D-RISM) theory, a statistical mechanics theory of molecular liquids. Numerical procedure for solving the conventional 3D-RISM equation consists of two steps. In step 1, we solve ordinary RISM (or 1D-RISM) equations for a solvent mixture including target ligands in order to obtain the density pair correlation functions (PCF) among molecules in the solution. Then, we solve the 3D-RISM equation for a solute-solvent system to find three-dimensional density distribution functions (3D-DDF) of solvent species around a protein, using PCF obtained in the first step. A key to the success of the method was to regard a target ligand as one of "solvent" species. However, the success is limited due to a difficulty of solving the 1D-RISM equation for a solvent mixture, including large ligand molecules. In the present paper, we propose a method which eases the limitation concerning solute size in the conventional method. In this approach, we solve a solute-solute 3D-RISM equations for a protein-ligand system in which both proteins and ligands are regarded as "solutes" at infinite dilution. The 3D- and 1D-RISM equations are solved for protein-solvent and ligand-solvent systems, respectively, in order to obtain the 3D- and 1D-DDF of solvent around the solutes, which are required for solving the solute-solute 3D-RISM equation. The method is applied to two practical and noteworthy examples concerning pharmaceutical design. One is an odorant binding protein in the Drosophila melanogaster , which binds an ethanol molecule. The other is phospholipase A2, which is known as a receptor of acetylsalicylic acid or aspirin. The result indicates that the method successfully reproduces the binding mode of the ligand molecules in the binding sites measured by the experiments.

Theoretical study of CO escaping pathway in myoglobin with the 3D-RISM theory.

CO escaping pathways of Myoglobin were investigated in terms of 3D distribution function which was calculated by the 3D-RISM theory. The partial molar volume changes through the CO escaping pathways show excellent agreement with those from the experiment.

A multicore QM/MM approach for the geometry optimization of chromophore aggregate in protein.

In this article, we present the multicore (mc) QM/MM method, a QM/MM method that can optimize the structure of chromophore aggregate in protein. A QM region is composed of the sum of the QM subregions that are small enough to apply practical electronic structure calculations. QM/MM energy gradient calculations are performed for each QM subregion. Several benchmark examinations were carried out to figure out availabilities and limitations. In the interregion distances of more than 3.5-4.0 A, the mcQM/MM energy gradient is very close to that obtained by the ordinary QM/MM method in which all the QM subregions were treated together as a single QM region. In van der Waals complex, the error exponentially drops with the distance, while the error decreases slowly in a hydrogen bonding complex. On the other hand, the optimized structures were reproduced with reasonable accuracy in both cases. The computational efficiency is the best advantage in the mcQM/MM approach, especially when the QM region is significantly large and the QM method used is computationally demanding. With this approach, we could optimize the structures of a bacterial photosynthetic reaction center protein in the ground and excited states, which consists of more than 14,000 atoms.