Theoretical Study of Solvent Effects on the Platinum-Catalyzed Oxygen Reduction Reaction

We report here density functional theory (DFT) studies (PBE) of the reaction intermediates and barriers involved in the oxygen reduction reaction (ORR) on a platinum fuel cell catalyst. Solvent effects were taken into account by applying continuum Poisson−Boltzmann theory to the bound adsorbates and to the transition states of the various reactions on the platinum (111) surface. Our calculations show that the solvent effects change significantly the reaction barriers compared with those in the gas-phase environment (without solvation). The O_2 dissociation barrier decreases from 0.58 to 0.27 eV, whereas the H + O → OH formation barrier increases from 0.73 to 1.09 eV. In the water-solvated phase, OH formation becomes the rate-determining step for both ORR mechanisms, O_2 dissociation and OOH association, proposed earlier for the gas-phase environment. Both mechanisms become significantly less favorable for the platinum catalytic surface in water solvent, suggesting that alternative mechanisms must be considered to describe properly the ORR on the platinum surface

A GPU-accelerated Direct-sum Boundary Integral Poisson-Boltzmann Solver

In this paper, we present a GPU-accelerated direct-sum boundary integral method to solve the linear Poisson-Boltzmann (PB) equation. In our method, a well-posed boundary integral formulation is used to ensure the fast convergence of Krylov subspace based linear algebraic solver such as the GMRES. The molecular surfaces are discretized with flat triangles and centroid collocation. To speed up our method, we take advantage of the parallel nature of the boundary integral formulation and parallelize the schemes within CUDA shared memory architecture on GPU. The schemes use only $11N+6N_c$ size-of-double device memory for a biomolecule with $N$ triangular surface elements and $N_c$ partial charges. Numerical tests of these schemes show well-maintained accuracy and fast convergence. The GPU implementation using one GPU card (Nvidia Tesla M2070) achieves 120-150X speed-up to the implementation using one CPU (Intel L5640 2.27GHz). With our approach, solving PB equations on well-discretized molecular surfaces with up to 300,000 boundary elements will take less than about 10 minutes, hence our approach is particularly suitable for fast electrostatics computations on small to medium biomolecules

Prediction of the most favorable configuration in the ACBP-membrane interaction based on electrostatic calculations

Acyl-CoA binding proteins (ACBPs) are highly conserved 10 kDa cytosolic proteins that bind medium- and long-chain acyl-CoA esters. They act as intracellular carriers of acyl-CoA and play a role in acyl-CoA metabolism, gene regulation, acyl-CoA-mediated cell signaling, transport-mediated lipid synthesis, membrane trafficking and also, ACBPs were indicated as a possible inhibitor of diazepam binding to the GABA-A receptor. To estimate the importance of the non-specific electrostatic energy in the ACBP-membrane interaction, we computationally modeled the interaction of HgACBP with both anionic and neutral membranes. To compute the Free Electrostatic Energy of Binding (dE), we used the Finite Difference Poisson Boltzmann Equation (FDPB) method as implemented in APBS. In the most energetically favorable orientation, ACBP brings charged residues Lys18 and Lys50 and hydrophobic residues Met46 and Leu47 into membrane surface proximity. This conformation suggests that these four ACBP amino acids are most likely to play a leading role in the ACBP-membrane interaction and ligand intake. Thus, we propose that long range electrostatic forces are the first step in the interaction mechanism between ACBP and membranes.Instituto de Física de Líquidos y Sistemas BiológicosFacultad de IngenieríaFacultad de Ciencias Exacta

Structure and RNA binding of the third KH domain of poly(C)-binding protein 1

Poly(C)-binding proteins (CPs) are important regulators of mRNA stability and translational regulation. They recognize C-rich RNA through their triple KH (hn RNP K homology) domain structures and are thought to carry out their function though direct protection of mRNA sites as well as through interactions with other RNA-binding proteins. We report the crystallographically derived structure of the third domain of αCP1 to 2.1 Å resolution. αCP1-KH3 assumes a classical type I KH domain fold with a triple-stranded β-sheet held against a three-helix cluster in a βααββα configuration. Its binding affinity to an RNA sequence from the 3′-untranslated region (3′-UTR) of androgen receptor mRNA was determined using surface plasmon resonance, giving a K(d) of 4.37 μM, which is indicative of intermediate binding. A model of αCP1-KH3 with poly(C)-RNA was generated by homology to a recently reported RNA-bound KH domain structure and suggests the molecular basis for oligonucleotide binding and poly(C)-RNA specificity

A Continuum Poisson-Boltzmann Model for Membrane Channel Proteins

Membrane proteins constitute a large portion of the human proteome and perform a variety of important functions as membrane receptors, transport proteins, enzymes, signaling proteins, and more. The computational studies of membrane proteins are usually much more complicated than those of globular proteins. Here we propose a new continuum model for Poisson-Boltzmann calculations of membrane channel proteins. Major improvements over the existing continuum slab model are as follows: 1) The location and thickness of the slab model are fine-tuned based on explicit-solvent MD simulations. 2) The highly different accessibility in the membrane and water regions are addressed with a two-step, two-probe grid labeling procedure, and 3) The water pores/channels are automatically identified. The new continuum membrane model is optimized (by adjusting the membrane probe, as well as the slab thickness and center) to best reproduce the distributions of buried water molecules in the membrane region as sampled in explicit water simulations. Our optimization also shows that the widely adopted water probe of 1.4 {\AA} for globular proteins is a very reasonable default value for membrane protein simulations. It gives an overall minimum number of inconsistencies between the continuum and explicit representations of water distributions in membrane channel proteins, at least in the water accessible pore/channel regions that we focus on. Finally, we validate the new membrane model by carrying out binding affinity calculations for a potassium channel, and we observe a good agreement with experiment results.Comment: 40 pages, 6 figures, 5 table

Structure Analysis of Entamoeba histolytica DNMT2 (EhMeth)

In eukaryotes, DNA methylation is an important epigenetic modification that is generally involved in gene regulation. Methyltransferases (MTases) of the DNMT2 family have been shown to have a dual substrate specificity acting on DNA as well as on three specific tRNAs (tRNAAsp, tRNAVal, tRNAGly). Entamoeba histolytica is a major human pathogen, and expresses a single DNA MTase (EhMeth) that belongs to the DNMT2 family and shows high homology to the human enzyme as well as to the bacterial DNA MTase M.HhaI. The molecular basis for the recognition of the substrate tRNAs and discrimination of non-cognate tRNAs is unknown. Here we present the crystal structure of the cytosine-5-methyltransferase EhMeth at a resolution of 2.15 Å, in complex with its reaction product S-adenosyl-L-homocysteine, revealing all parts of a DNMT2 MTase, including the active site loop. Mobility shift assays show that in vitro the full length tRNA is required for stable complex formation with EhMeth

Exploring a coarse-grained distributive strategy for finite-difference Poisson–Boltzmann calculations

We have implemented and evaluated a coarse-grained distributive method for finite-difference Poisson–Boltzmann (FDPB) calculations of large biomolecular systems. This method is based on the electrostatic focusing principle of decomposing a large fine-grid FDPB calculation into multiple independent FDPB calculations, each of which focuses on only a small and a specific portion (block) of the large fine grid. We first analyzed the impact of the focusing approximation upon the accuracy of the numerical reaction field energies and found that a reasonable relative accuracy of 10−3 can be achieved when the buffering space is set to be 16 grid points and the block dimension is set to be at least (1/6)3 of the fine-grid dimension, as in the one-block focusing method. The impact upon efficiency of the use of buffering space to maintain enough accuracy was also studied. It was found that an “optimal” multi-block dimension exists for a given computer hardware setup, and this dimension is more or less independent of the solute geometries. A parallel version of thedistributive focusing method was also implemented. Given the proper settings, the distributive method was able to achieve respectable parallel efficiency with tested biomolecular systems on a loosely connected computer cluster

Prediction of the most favorable configuration in the ACBP-membrane interaction based on electrostatic calculations

Acyl-CoA binding proteins (ACBPs) are highly conserved 10 kDa cytosolic proteins that bind medium- and long-chain acyl-CoA esters. They act as intracellular carriers of acyl-CoA and play a role in acyl-CoA metabolism, gene regulation, acyl-CoA-mediated cell signaling, transport-mediated lipid synthesis, membrane trafficking and also, ACBPs were indicated as a possible inhibitor of diazepam binding to the GABA-A receptor. To estimate the importance of the non-specific electrostatic energy in the ACBP-membrane interaction, we computationally modeled the interaction of HgACBP with both anionic and neutral membranes. To compute the Free Electrostatic Energy of Binding (dE), we used the Finite Difference Poisson Boltzmann Equation (FDPB) method as implemented in APBS. In the most energetically favorable orientation, ACBP brings charged residues Lys18 and Lys50 and hydrophobic residues Met46 and Leu47 into membrane surface proximity. This conformation suggests that these four ACBP amino acids are most likely to play a leading role in the ACBP-membrane interaction and ligand intake. Thus, we propose that long range electrostatic forces are the first step in the interaction mechanism between ACBP and membranes.Instituto de Física de Líquidos y Sistemas BiológicosFacultad de IngenieríaFacultad de Ciencias Exacta

Acceleration of Linear Finite-Difference Poisson-Boltzmann Methods on Graphics Processing Units

Electrostatic interactions play crucial roles in biophysical processes such as protein folding and molecular recognition. Poisson-Boltzmann equation (PBE)-based models have emerged as widely used in modeling these important processes. Though great efforts have been put into developing efficient PBE numerical models, challenges still remain due to the high dimensionality of typical biomolecular systems. In this study, we implemented and analyzed commonly used linear PBE solvers for the ever-improving graphics processing units (GPU) for biomolecular simulations, including both standard and preconditioned conjugate gradient (CG) solvers with several alternative preconditioners. Our implementation utilizes standard Nvidia CUDA libraries cuSPARSE, cuBLAS, and CUSP. Extensive tests show that good numerical accuracy can be achieved given that the single precision is often used for numerical applications on GPU platforms. The optimal GPU performance was observed with the Jacobi-preconditioned CG solver, with a significant speedup over standard CG solver on CPU in our diversified test cases. Our analysis further shows that different matrix storage formats also considerably affect the efficiency of different linear PBE solvers on GPU, with the diagonal format best suited for our standard finite-difference linear systems. Further efficiency may be possible with matrix-free operations and integrated grid stencil setup specifically tailored for the banded matrices in PBE-specific linear systems.Comment: 5 figures, 2 table