PKA17-A Coarse-Grain Grid-Based Methodology and Web-Based Software for Predicting Protein pK Shifts.

We have developed and tested PKA17, a coarse-grain grid-based model for predicting protein pK shifts. Our pK predictor is currently deployed via a website interface. We have carried out parameter fitting using 442 Asp, Glu, His, Lys, and Arg residues for which experimental results are available in the literature.

Binding of Copper and Cisplatin to Atox1 Is Mediated by Glutathione through the Formation of Metal-Sulfur Clusters.

Copper is an essential nutrient required for many biological processes involved in primary metabolism, but free copper is toxic due to its ability to catalyze formation of free radicals. To prevent toxic effects, in the cell copper is bound to proteins and low molecular weight compounds, such as glutathione, at all times. The widely used chemotherapy agent cisplatin is known to bind to copper-transporting proteins, including copper chaperone Atox1.

Developing multisite empirical force field models for Pt(II) and cisplatin.

We have developed empirical force field parameters for Pt(II) and cisplatin. Two force field frameworks were used-modified OPLS-AA and our second-order polarizable POSSIM. A seven-site model was used for the Pt(II) ion.

Using polarizable POSSIM force field and fuzzy-border continuum solvent model to calculate pK(a) shifts of protein residues.

Our Fuzzy-Border (FB) continuum solvent model has been extended and modified to produce hydration parameters for small molecules using POlarizable Simulations Second-order Interaction Model (POSSIM) framework with an average error of 0.136 kcal/mol. It was then used to compute pK shifts for carboxylic and basic residues of the turkey ovomucoid third domain (OMTKY3) protein.

Computational Studies of the Effect of Shock Waves on the Binding of Model Complexes.

We have simulated effects of a shock wave in water that would result from the collapse of a cavitation bubble on binding in model complexes. We have considered a benzene dimer, a pair of uracil molecules, a complex of fragments of the X-linked inhibitor of apoptosis and caspase-9, and a fragment of c-Myc oncoprotein in binding with its dimerization partner Max. The effect of the shock waves was simulated by adding a momentum to a slab of solvent water molecules and observing the system as the slab moved and caused changes.

POSSIM: Parameterizing Complete Second-Order Polarizable Force Field for Proteins.

Previously, we reported development of a fast polarizable force field and software named POSSIM (POlarizable Simulations with Second order Interaction Model). The second-order approximation permits the speed up of the polarizable component of the calculations by ca. an order of magnitude.

Effects of lysine substitution on stability of polyalanine alpha-helix.

We have studied stability of polyalanine alpha-helices with lysine residues added at C-and N-termini in gas-phase and aqueous solution. Monte Carlo simulations with the fixed-charges OPLS-AA and our polarizable POSSIM force fields were carried out. The results of the simulations confirm previously observed phenomena of the helix being stable with the LYS residue on the C-terminus and losing its helical structure if the charged LYS residue is located at the N-terminus of the polypeptide in gas-hase.

Polarizable simulations with second order interaction model (POSSIM) force field: developing parameters for protein side-chain analogues.

A previously introduced polarizable simulations with second-order interaction model (POSSIM) force field has been extended to include parameters for small molecules serving as models for peptide and protein side-chains. Parameters have been fitted to permit reproducing many-body energies, gas-phase dimerization energies, and geometries and liquid-phase heats of vaporization and densities. Quantum mechanical and experimental data have been used as the target for the fitting.

Calculating pKa values for substituted phenols and hydration energies for other compounds with the first-order Fuzzy-Border continuum solvation model.

We have computed pK(a) values for 11 substituted phenol compounds using the continuum Fuzzy-Border (FB) solvation model. Hydration energies for 40 other compounds, including alkanes, alkenes, alkynes, ketones, amines, alcohols, ethers, aromatics, amides, heterocycles, thiols, sulfides, and acids have been calculated. The overall average unsigned error in the calculated acidity constant values was equal to 0.

Importance of electrostatic polarizability in calculating cysteine acidity constants and copper(I) binding energy of Bacillus subtilis CopZ.

CopZ is a copper chaperone from Bacillus subtilis. It is an important part of Cu(I) trafficking. We have calculated pK(a) values for the CXXC motif of this protein, which is responsible for the Cu(I) binding, and the Cu(I) binding constants.

Electrostatic polarization is crucial in reproducing Cu(I) interaction energies and hydration.

We have explored the suitability of fixed-charges and polarizable force fields for modeling interactions of the monovalent Cu(I) ion. Parameters for this ion have been tested and refitted within the fixed-charges OPLS-AA and polarizable force field (PFF) frameworks. While this ion plays an important role in many protein interactions, the attention to it in developing empirical force fields is limited.

Polarizable Simulations with Second order Interaction Model (POSSIM) force field: Developing parameters for alanine peptides and protein backbone.

A previously introduced POSSIM (POlarizable Simulations with Second order Interaction Model) force field has been extended to include parameters for alanine peptides and protein backbones. New features were introduced into the fitting protocol, as compared to the previous generation of the polarizable force field for proteins. A reduced amount of quantum mechanical data was employed in fitting the electrostatic parameters.

Quality of random number generators significantly affects results of Monte Carlo simulations for organic and biological systems.

We have simulated pure liquid butane, methanol, and hydrated alanine polypeptide with the Monte Carlo technique using three kinds of random number generators (RNG's)-the standard Linear Congruential Generator (LCG), a modification of the LCG with additional randomization used in the BOSS software, and the "Mersenne Twister" generator by Matsumoto and Nishimura. While using the latter two RNG's leads to reasonably similar physical features, the LCG produces significant different results. For the pure fluids, a noticeable expansion occurs.

Polarizable Simulations with Second order Interaction Model - force field and software for fast polarizable calculations: Parameters for small model systems and free energy calculations.

We are presenting POSSIM (POlarizable Simulations with Second order Interaction Model) - a software package and a set of parameters designed for molecular simulations. The key feature of POSSIM is that the electrostatic polarization is taken into account using a previously introduced fast formalism. This permits cutting computational cost of using the explicit polarization by about an order of magnitude.

Reproducing basic pKa values for turkey ovomucoid third domain using a polarizable force field.

We have extended our previous studies of calculating acidity constants for the acidic residues found in the turkey ovomucoid third domain protein (OMTKY3) by determining the relative pKa values for the basic residues (Lys13, Arg21, Lys29, Lys34, His52, and Lys55). A polarizable force field (PFF) was employed. The values of the pKa were found by direct comparison of energies of solvated protonated and deprotonated forms of the protein.

Computational Studies of the X-Linked Inhibitor of Apoptosis Complex Formation with Caspase-9 and a Small Antagonist.

Apoptosis is self-programmed cell death. The X-linked inhibitor of apoptosis (XIAP) is known to inhibit caspase proteins, the key players in apoptosis. When this happens, the cells become cancerous as they cannot die naturally.

Electrostatic polarization is crucial for reproducing pKa shifts of carboxylic residues in Turkey ovomucoid third domain.

We have computed pKa shifts for carboxylic residues of the serine protease inhibitor turkey ovomucoid third domain (residues Asp7, Glu10, Glu19, Asp27, and Glu43). Both polarizable and nonpolarizable empirical force fields were employed. Hydration was represented by the surface generalized Born and Poisson-Boltzmann continuum model.

Accurate determination of pyridine-poly(amidoamine) dendrimer absolute binding constants with the OPLS-AA force field and direct integration of radial distribution functions.

OPLS-AA force field and direct integration of intermolecular radial distribution functions (RDF) were employed to calculate absolute binding constants of pyridine molecules to amino group (NH2) and amide group hydrogen atoms in and first generation poly(amidoamine) dendrimers in chloroform. The average errors in the absolute and relative association constants, as predicted with the calculations, are 14.1% and 10.

Accurate prediction of absolute acidity constants in water with a polarizable force field: substituted phenols, methanol, and imidazole.

Validity of a force field with explicit treatment of electrostatic polarization in a form of inducible point dipoles for computing acidity constants was tested by calculating absolute pK(a) values of substituted phenols, methanol, and imidazole in water with the molecular dynamics technique. The last two systems were selected as tyrosine and histidine side-chain analogues, respectively. The solvent was represented by an explicit polarizable water model.

A Polarizable Force Field and Continuum Solvation Methodology for Modeling of Protein-Ligand Interactions.

A polarizable force field, and associated continuum solvation model, have been developed for the explicit purpose of computing and studying the energetics and structural features of protein binding to the wide range of ligands with potential for medicinal applications. Parameters for the polarizable force field (PFF) are derived from gas-phase ab initio calculations and then utilized for applications in which the protein binding to ligands occurs in aqueous solvents, wherein the charge distributions of proteins and ligands can be dramatically altered. The continuum solvation model is based on a self-consistent reaction field description of solvation, incorporating an analytical gradient, that allows energy minimizations (and, potentially, molecular dynamics simulations) of protein/ligand systems in continuum solvent.

Pseudospectral Local Second-Order Møller-Plesset Methods for Computation of Hydrogen Bonding Energies of Molecular Pairs.

We present a methodology for computing the binding energy of molecular dimers based on extrapolation of pseudospectral local second-order Moller-Plesset (MP2), or PS-LMP2, energies to the basis set limit. The extrapolation protocol is based on carrying out PS-LMP2 calculations with the Dunning cc-pVTZ (-f) and cc-pVQZ (-g) basis sets and then using a simple two-parameter function to compute the final basis set limit results. The function is parametrized to ultralarge basis set MP2 calculations for 5 molecular pairs taken from the literature and then tested by calculating results for a set of formamide dimers for which such calculations have also been carried out.

A computationally inexpensive modification of the point dipole electrostatic polarization model for molecular simulations.

We present an approximation, which allows reduction of computational resources needed to explicitly incorporate electrostatic polarization into molecular simulations utilizing empirical force fields. The proposed method is employed to compute three-body energies of molecular complexes with dipolar electrostatic probes, gas-phase dimerization energies, and pure liquid properties for five systems that are important in biophysical and organic simulations-water, methanol, methylamine, methanethiol, and acetamide. In all the cases, the three-body energies agreed with high level ab initio data within 0.

Development of a polarizable force field for proteins via ab initio quantum chemistry: first generation model and gas phase tests.

We present results of developing a methodology suitable for producing molecular mechanics force fields with explicit treatment of electrostatic polarization for proteins and other molecular system of biological interest. The technique allows simulation of realistic-size systems. Employing high-level ab initio data as a target for fitting allows us to avoid the problem of the lack of detailed experimental data.