Protein/ligand binding free energies calculated with quantum mechanics/molecular mechanics.

The calculation of binding affinities for flexible ligands has hitherto required the availability of reliable molecular mechanics parameters for the ligands, a restriction that can in principle be lifted by using a mixed quantum mechanics/molecular mechanics (QM/MM) representation in which the ligand is treated quantum mechanically. The feasibility of this approach is evaluated here, combining QM/MM with the Poisson-Boltzmann/surface area model of continuum solvation and testing the method on a set of 47 benzamidine derivatives binding to trypsin. The experimental range of the absolute binding energy (DeltaG = -3.

Insights into the chemomechanical coupling of the myosin motor from simulation of its ATP hydrolysis mechanism.

The molecular motor myosin converts chemical energy from ATP hydrolysis into mechanical work, thus driving a variety of essential motility processes. Although myosin function has been studied extensively, the catalytic mechanism of ATP hydrolysis and its chemomechanical coupling to the motor cycle are not completely understood. Here, the catalysis mechanism in myosin II is examined using quantum mechanical/molecular mechanical reaction path calculations.

Molecular modeling of O6-methylguanine-DNA methyltransferase mutant proteins encoded by single nucleotide polymorphisms.

The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) acts as a chemoprotectant and mediates resistance to alkylating anti-tumor agents. A number of MGMT single nucleotide polymorphisms (SNPs) have been described. We analyzed by molecular modeling the regions likely to be affected in the MGMT mutant proteins encoded by SNPs.

Nonuniform charge scaling (NUCS): a practical approximation of solvent electrostatic screening in proteins.

In molecular mechanics calculations, electrostatic interactions between chemical groups are usually represented by a Coulomb potential between the partial atomic charges of the groups. In aqueous solution these interactions are modified by the polarizable solvent. Although the electrostatic effects of the polarized solvent on the protein are well described by the Poisson--Boltzmann equation, its numerical solution is computationally expensive for large molecules such as proteins.

Computational tools for analysing structural changes in proteins in solution.

Many important structural changes in proteins involve long-time dynamics, which are outside the timescale presently accessible by a straightforward integration of Newton's equations of motion. This problem is addressed with minimisation-based algorithms, which are applied on possible reaction pathways using atomic-detail models. For reasons of efficiency, an implicit treatment of solvent is imperative.

How well does charge reparametrisation account for solvent screening in molecular mechanics calculations? The example of myosin.

The rate constant of an enzyme-catalysed reaction is one of the major target properties to understand protein function. Atomic-detail computer simulations can in principle be used to estimate rate constants from the energy profile along the reaction coordinate. For such simulations, molecular mechanics is combined with a quantum description of the reaction process.

Time-resolved computational protein biochemistry: solvent effects on interactions, conformational transitions and equilibrium fluctuations.

Solvent plays an important role in modulating internal motions of proteins. Here we present a computational method for including solvent effects on charge-charge interactions and on pathways between functional protein conformations, and examine solvent effects on equilibrium internal fluctuations in proteins. A computationally efficient charge reparametrisation method is presented that satisfactorily reproduces the electrostatic interactions present in a full continuum Poisson-Boltzmann representation.

Can the calculation of ligand binding free energies be improved with continuum solvent electrostatics and an ideal-gas entropy correction?

The prediction of a ligand binding constant requires generating three-dimensional structures of the complex concerned and reliably scoring these structures. Here, the scoring problem is investigated by examining benzamidine-like inhibitors of trypsin, a system for which errors in the structures are small. Precise and consistent binding free energies for the inhibitors are determined experimentally for this test system.