Thom Vreven

Combining quantum mechanics methods with molecular mechanics methods in ONIOM

The purpose of this paper is 2-fold. First, we present several extensions to the ONIOM(QM:MM) scheme. In its original formulation, the electrostatic interaction between the regions is included at the classical level. Here we present the extension to electronic embedding. We show how the behavior of ONIOM with electronic embedding can be more stable than QM/MM with electronic embedding. We also investigate the link atom correction, which is implicit in ONIOM but not in QM/MM. Second, we demonstrate some of the practical aspects of ONIOM(QM:MM) calculations. Specifically, we show that the potential surface can be discontinuous when there is bond breaking and forming closer than three bonds from the MM region.

Geometry optimization with QM/MM, ONIOM, and other combined methods. I. Microiterations and constraints

Hybrid energy methods such as QM/MM and ONIOM, that combine different levels of theory into one calculation, have been very successful in describing large systems. Geometry optimization methods can take advantage of the partitioning of these calculations into a region treated at a quantum mechanical (QM) level of theory and the larger, remaining region treated by an inexpensive method such as molecular mechanics (MM). A series of microiterations can be employed to fully optimize the MM region for each optimization step in the QM region. Cartesian coordinates are used for the MM region and are chosen so that the internal coordinates of the QM region remain constant during the microiterations. The coordinates of the MM region are augmented to permit rigid body translation and rotation of the QM region. This is essential if any atoms in the MM region are constrained, but it also improves the efficiency of unconstrained optimizations. Because of the microiterations, special care is needed for the optimization step in the QM region so that the system remains in the same local valley during the course of the optimization. The optimization methodology with microiterations, constraints, and step‐size control are illustrated by calculations on bacteriorhodopsin and other systems.

On the application of the IMOMO (integrated molecular orbital + molecular orbital) method

Five years ago Morokuma and colleagues introduced the IMOMO method, which integrates two molecular orbital methods into one calculation. Since then, the method has been expanded in several ways; it has been generalized to consider up to three methods, and has been unified as the ONIOM method to include both MO and MM combinations. In this review we present the history of the method, a number of chemical problems that we have studied, how to assess IMOMO combinations and partitionings, and our latest efforts that take the method beyond the conventional investigation of ground state energy surfaces. In particular, we emphasize the importance of the S‐value test for validation of the ONIOM method/model combinations. The method combination depends much on the properties and accuracies required. Generally speaking, however, if the target level is CCSD(T) or G2, the best choice of low level is MP2. If MP2 or DFT is the target level, HF or eventually semiempirical MO methods are good choices of low level. These methods can be further combined with an outer‐most layer of the MM level.

ZDOCK server: interactive docking prediction of protein-protein complexes and symmetric multimers.

SUMMARY Protein-protein interactions are essential to cellular and immune function, and in many cases, because of the absence of an experimentally determined structure of the complex, these interactions must be modeled to obtain an understanding of their molecular basis. We present a user-friendly protein docking server, based on the rigid-body docking programs ZDOCK and M-ZDOCK, to predict structures of protein-protein complexes and symmetric multimers. With a goal of providing an accessible and intuitive interface, we provide options for users to guide the scoring and the selection of output models, in addition to dynamic visualization of input structures and output docking models. This server enables the research community to easily and quickly produce structural models of protein-protein complexes and symmetric multimers for their own analysis. AVAILABILITY The ZDOCK server is freely available to all academic and non-profit users at: http://zdock.umassmed.edu. No registration is required.

A direct derivative MC-SCF procedure

Abstract A direct method for the computation of energy second derivatives, and first derivatives which require the solution of the coupled perturbed MC-SCF equations, is presented. The two-electron derivative integral transformation is formulated in terms of 3/4 transformed integrals. The optimum strategy for the solution of the CP-MCSCF linear equations involves the solution in a Krylov space that involves all the right-hand sides. The feasibility of the method is demonstrated in a computation on the excited states of indene, styrene and octatetraene.

The ONIOM-PCM method: Combining the hybrid molecular orbital method and the polarizable continuum model for solvation. Application to the geometry and properties of a merocyanine in solution

We present the ONIOM-PCM method, which combines the ONIOM (our own n-layered integrated molecular orbital+molecular mechanics) method with the polarizable continuum model (PCM). Four versions of the method have been developed. These schemes differ mainly with respect to the level of coupling between the solute charge distribution and the continuum, which has important consequences for the computational efficiency. Any property that can be calculated by both ONIOM and PCM can also be calculated by the ONIOM-PCM method. In the current paper we use this aspect for the calculation of the derivatives of the energy with respect to the nuclear coordinates to perform geometry optimizations, and the calculation of the nuclear magnetic resonance shielding for solvated molecules. To assess the various versions of the method, we performed ONIOM(B3LYP:Hartree–Fock)-PCM calculations on a merocyanine, H2N(C2H2)3CHO. All four schemes yield results close to the target B3LYP (three-parameter Becke–Lee–Yang–Parr density fun...

Community-wide assessment of protein-interface modeling suggests improvements to design methodology

The CAPRI (Critical Assessment of Predicted Interactions) and CASP (Critical Assessment of protein Structure Prediction) experiments have demonstrated the power of community-wide tests of methodology in assessing the current state of the art and spurring progress in the very challenging areas of protein docking and structure prediction. We sought to bring the power of community-wide experiments to bear on a very challenging protein design problem that provides a complementary but equally fundamental test of current understanding of protein-binding thermodynamics. We have generated a number of designed protein-protein interfaces with very favorable computed binding energies but which do not appear to be formed in experiments, suggesting that there may be important physical chemistry missing in the energy calculations. A total of 28 research groups took up the challenge of determining what is missing: we provided structures of 87 designed complexes and 120 naturally occurring complexes and asked participants to identify energetic contributions and/or structural features that distinguish between the two sets. The community found that electrostatics and solvation terms partially distinguish the designs from the natural complexes, largely due to the nonpolar character of the designed interactions. Beyond this polarity difference, the community found that the designed binding surfaces were, on average, structurally less embedded in the designed monomers, suggesting that backbone conformational rigidity at the designed surface is important for realization of the designed function. These results can be used to improve computational design strategies, but there is still much to be learned; for example, one designed complex, which does form in experiments, was classified by all metrics as a nonbinder.

UAP56 couples piRNA clusters to the perinuclear transposon silencing machinery

piRNAs silence transposons during germline development. In Drosophila, transcripts from heterochromatic clusters are processed into primary piRNAs in the perinuclear nuage. The nuclear DEAD box protein UAP56 has been previously implicated in mRNA splicing and export, whereas the DEAD box protein Vasa has an established role in piRNA production and localizes to nuage with the piRNA binding PIWI proteins Ago3 and Aub. We show that UAP56 colocalizes with the cluster-associated HP1 variant Rhino, that nuage granules containing Vasa localize directly across the nuclear envelope from cluster foci containing UAP56 and Rhino, and that cluster transcripts immunoprecipitate with both Vasa and UAP56. Significantly, a charge-substitution mutation that alters a conserved surface residue in UAP56 disrupts colocalization with Rhino, germline piRNA production, transposon silencing, and perinuclear localization of Vasa. We therefore propose that UAP56 and Vasa function in a piRNA-processing compartment that spans the nuclear envelope.

Chapter 3 Hybrid Methods: ONIOM(QM:MM) and QM/MM

Publisher Summary This chapter discusses the history of hybrid methods, the main differences between the various schemes, and the way they are used for the investigation of potential surfaces or properties. The chapter focuses on a hybrid method, called “ONIOM,” which can in principle use any computational method and do so for any number of layers. Most methods can only combine a quantum mechanical (QM) method with a MM method, which is generally referred to as “QM/MM.” Only several hybrid methods can also combine QM with QM or more than two different computational methods. The hybrid methods offer a solution to the scaling problem. Although the foundation for QM/MM potentials is laid much earlier, practical ways for using the surfaces needs to be developed. The number of application and post-potential methods studies is increased much relative to the attention for QM–MM interaction terms and capping methods. Judging from the continuous work, QM/MM methods will eventually impact almost every field of chemistry.

The HP1 Homolog Rhino Anchors a Nuclear Complex that Suppresses piRNA Precursor Splicing

piRNAs guide an adaptive genome defense system that silences transposons during germline development. The Drosophila HP1 homolog Rhino is required for germline piRNA production. We show that Rhino binds specifically to the heterochromatic clusters that produce piRNA precursors, and that binding directly correlates with piRNA production. Rhino colocalizes to germline nuclear foci with Rai1/DXO-related protein Cuff and the DEAD box protein UAP56, which are also required for germline piRNA production. RNA sequencing indicates that most cluster transcripts are not spliced and that rhino, cuff, and uap56 mutations increase expression of spliced cluster transcripts over 100-fold. LacI::Rhino fusion protein binding suppresses splicing of a reporter transgene and is sufficient to trigger piRNA production from a trans combination of sense and antisense reporters. We therefore propose that Rhino anchors a nuclear complex that suppresses cluster transcript splicing and speculate that stalled splicing differentiates piRNA precursors from mRNAs.