Daan P. Geerke

The GROMOS software for biomolecular simulation: GROMOS05

We present the latest version of the Groningen Molecular Simulation program package, GROMOS05. It has been developed for the dynamical modelling of (bio)molecules using the methods of molecular dynamics, stochastic dynamics, and energy minimization. An overview of GROMOS05 is given, highlighting features not present in the last major release, GROMOS96. The organization of the program package is outlined and the included analysis package GROMOS++ is described. Finally, some applications illustrating the various available functionalities are presented.

GROMOS++ Software for the Analysis of Biomolecular Simulation Trajectories

GROMOS++ is a set of C++ programs for pre- and postprocessing of molecular dynamics simulation trajectories and as such is part of the GROningen MOlecular Simulation software for (bio)molecular simulation. It contains more than 70 programs that can be used to prepare data for the production of molecular simulation trajectories and to analyze these. These programs are reviewed and the various structural, dynamic, and thermodynamic quantities that can be analyzed using time series, correlation functions, and distributions are described together with technical aspects of their implementation in GROMOS. A few examples of the use of GROMOS++ for the analysis of MD trajectories are given. A full list of all GROMOS++ programs, together with an indication of their capabilities, is given in the Appendix .

Impaired bortezomib binding to mutant beta 5 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells.

Proteasome inhibition is a novel treatment for several hematological malignancies. However, resistance to the proteasome inhibitor bortezomib (BTZ, Velcade) is an emerging clinical impediment. Mutations in the β5 subunit of the proteasome, the primary target of BTZ, have been associated with drug resistance. However, the exact mechanism by which these mutations contribute to BTZ resistance, is still largely unknown. Toward this end, we here developed BTZ-resistant multiple myeloma (8226) and acute lymphoblastic leukemia (CCRF-CEM) cell line models by exposure to stepwise increasing concentrations of BTZ. Characterization of the various BTZ-resistant cells revealed upregulation of mutant β5 subunit of the proteasome. These newly identified β5-subunit mutations, along with previously described mutations, formed a mutation cluster region in the BTZ-binding pocket of the β5 subunit, that of the S1 specificity pocket in particular. Moreover, we provide the first evidence that the mechanism underlying BTZ resistance in these tumor cells is impaired binding of BTZ to the mutant β5 subunit of the proteasome. We propose that proteasome subunit overexpression is an essential compensatory mechanism for the impaired catalytic activity of these mutant proteasomes. Our findings further suggest that second-generation proteasome inhibitors that target the α7 subunit of the proteasome can overcome this drug resistance modality.

Molecular dynamics simulations of liquid methanol and methanol–water mixtures with polarizable models

A polarizable model for simulation of liquid methanol, compatible with the COS/G2 water model, has been developed using the Charge‐on‐Spring (COS) technique. The model consists of three point charges, with one polarizable center on the oxygen atom. The Lennard–Jones parameters on the oxygen atom together with the molecular polarizability were varied to reproduce the experimental heat of vaporization and density of liquid methanol at ambient conditions. We examined the energies of various methanol dimers in the gas phase and compared them with values obtained from ab initio calculations. The model was then used to study the thermodynamic, dynamic, structural, and dielectric properties of liquid methanol as well as of a methanol–water mixture. A microscopic picture of the structure of pure liquid methanol and of the methanol–water mixture is provided. Good agreement was found between the results from our model simulations and available experimental and ab initio calculation data. In particular, the experimental dielectric permittivity of 32 could be reproduced, which had been shown to be difficult when using nonpolarizable models.

New functionalities in the GROMOS biomolecular simulation software

Since the most recent description of the functionalities of the GROMOS software for biomolecular simulation in 2005 many new functions have been implemented. In this article, the new functionalities that involve modified forces in a molecular dynamics (MD) simulation are described: the treatment of electronic polarizability, an implicit surface area and internal volume solvation term to calculate interatomic forces, functions for the GROMOS coarse‐grained supramolecular force field, a multiplicative switching function for nonbonded interactions, adiabatic decoupling of a number of degrees of freedom with temperature or force scaling to enhance sampling, and nonequilibrium MD to calculate the dielectric permittivity or viscosity. Examples that illustrate the use of these functionalities are given.

Charge Group Partitioning in Biomolecular Simulation

Molecular simulation techniques are increasingly being used to study biomolecular systems at an atomic level. Such simulations rely on empirical force fields to represent the intermolecular interactions. There are many different force fields available--each based on a different set of assumptions and thus requiring different parametrization procedures. Recently, efforts have been made to fully automate the assignment of force-field parameters, including atomic partial charges, for novel molecules. In this work, we focus on a problem arising in the automated parametrization of molecules for use in combination with the GROMOS family of force fields: namely, the assignment of atoms to charge groups such that for every charge group the sum of the partial charges is ideally equal to its formal charge. In addition, charge groups are required to have size at most k. We show NP-hardness and give an exact algorithm that solves practical problem instances to provable optimality in a fraction of a second.

Oxidative addition of the ethane C-C bond to Pd. An ab initio benchmark and DFT validation study

We have computed a state‐of‐the‐art benchmark potential energy surface (PES) for the archetypal oxidative addition of the ethane CC bond to the palladium atom and have used this to evaluate the performance of 24 popular density functionals, covering LDA, GGA, meta‐GGA, and hybrid density functionals, for describing this reaction. The ab initio benchmark is obtained by exploring the PES using a hierarchical series of ab initio methods [HF, MP2, CCSD, CCSD(T)] in combination with a hierarchical series of five Gaussian‐type basis sets, up to g polarization. Relativistic effects are taken into account either through a relativistic effective core potential for palladium or through a full four‐component all‐electron approach. Our best estimate of kinetic and thermodynamic parameters is −10.8 (−11.3) kcal/mol for the formation of the reactant complex, 19.4 (17.1) kcal/mol for the activation energy relative to the separate reactants, and −4.5 (−6.8) kcal/mol for the reaction energy (zero‐point vibrational energy‐corrected values in parentheses). Our work highlights the importance of sufficient higher angular momentum polarization functions for correctly describing metal‐d‐electron correlation. Best overall agreement with our ab initio benchmark is obtained by functionals from all three categories, GGA, meta‐GGA, and hybrid DFT, with mean absolute errors of 1.5 to 2.5 kcal/mol and errors in activation energies ranging from −0.2 to −3.2 kcal/mol. Interestingly, the well‐known BLYP functional compares very reasonably with a slight underestimation of the overall barrier by −0.9 kcal/mol. For comparison, with B3LYP we arrive at an overestimation of the overall barrier by 5.8 kcal/mol. On the other hand, B3LYP performs excellently for the central barrier (i.e., relative to the reactant complex) which it underestimates by only −0.1 kcal/mol.

Combined QM/MM Molecular Dynamics Study on a Condensed-Phase SN2 Reaction at Nitrogen: The Effect of Explicitly Including Solvent Polarization.

In a previous combined QM/MM molecular dynamics (MD) study from our laboratory on the identity SN2 reaction between a chloride anion and an amino chloride in liquid dimethyl ether (DME), an increase in the free energy activation barrier was observed in the condensed phase when compared to the gas-phase activation energy. Here we reproduce these findings, but when comparing the condensed-phase potential of mean force (PMF) with the free energy profile in the gas phase (obtained from Monte Carlo simulations), we observe a smaller solvent effect on the activation barrier of the reaction. In a next step, we introduce an explicit description of electronic polarization in the MM (solvent) part of the system. A polarizable force field for liquid DME was developed based on the charge-on-spring (COS) model, which was calibrated to reproduce thermodynamic properties of the nonpolarizable model in classical MD simulations. The COS model was implemented into the MNDO/GROMOS interface in a special version of the QM/MM software ChemShell, which was used to investigate the effect of solvent polarization on the free energy profile of the reaction under study. A higher activation barrier was obtained using the polarizable solvent model than with the nonpolarizable force field, due to a better solvation of and a stronger polarization of solvent molecules around the separate reactants. The obtained PMFs were subjected to an energy-entropy decomposition of the relative solvation free energies of the reactant complex along the reaction coordinate, to investigate in a quantitative manner whether the solvent (polarization) effects are mainly due to favorable QM-MM (energetic) interactions.

The performance of non-polarizable and polarizable force-field parameter sets for ethylene glycol in molecular dynamics simulations of the pure liquid and its aqueous mixtures

Non-polarizable and polarizable force-field parameter sets for liquid ethylene glycol (EG) were developed for use in biomolecular simulation. In the polarizable models, electronic polarization effects were explicitly taken into account using the charge-on-spring method. The quality of the new force fields and two non-polarizable EG models taken from the literature was investigated by calculating relevant properties of the pure liquid and its aqueous mixtures, and comparing simulation results with experimental data. The performance of the EG models as a co-solvent in aqueous mixtures was additionally evaluated in a hydrophobic hydration study. The question was whether the experimentally known maximum in the solvation free enthalpy of argon at intermediate mixture compositions could be reproduced in the simulations. Values for the dielectric properties and excess free energy were found to be more off from experiment for the polarizable models than for the non-polarizable ones. However, a Kirkwood–Buff analysis of the aqueous mixtures and the hydrophobic hydration results exemplified that electronic polarization plays an important role in correctly describing attractive interactions between the EG and water co-solvent molecules. The trans/gauche ratio for ethylene glycols O–C–C–O torsional angle was not found to systematically affect the properties of the pure liquid and aqueous mixtures.

A single active site mutation inverts stereoselectivity of 16-hydroxylation of testosterone catalyzed by engineered cytochrome P450 BM3.

Inversion of stereoselectivity: screening of a minimal mutant library revealed a cytochrome P450 BM3 variant M01 A82W S72I capable of producing 16 α-OH-testosterone. Remarkably, a single active site mutation S72I in M01 A82W inverted the stereoselectivity of hydroxylation from 16 β to 16 α. Introduction of S72I mutation in another 16 β-OH-selective variant M11 V87I, also resulted in similar inversion of stereoselectivity.