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BACKGROUND An important prerequisite for computational structure-based drug design is prediction of the structures of ligand-protein complexes that have not yet been experimentally determined by X-ray crystallography or NMR. For this task, docking of rigid ligands is inadequate because it assumes knowledge of the conformation of the bound ligand. Docking of(More)
A new procedure for molecular replacement is presented in which an efficient six-dimensional search is carried out using an evolutionary optimization algorithm. In this procedure, a population of initially random molecular-replacement solutions is iteratively optimized with respect to the correlation coefficient between observed and calculated structure(More)
Common failures in predicting crystal structures of ligand-protein complexes are investigated for three ligand-protein systems by a combined thermodynamic and kinetic analysis of the binding energy landscapes. Misdocked predictions in ligand-protein docking are classified as 'soft' and 'hard' failures. While a soft failure arises when the search algorithm(More)
The identification of phospholipidosis (PPL) during preclinical testing in animals is a recognized problem in the pharmaceutical industry. Depending on the intended indication and dosing regimen, PPL can delay or stop development of a compound in the drug discovery process. Therefore, for programs and projects where a PPL finding would have adverse impact(More)
The energy landscape approach has contributed to recent progress in understanding the complexity and simplicity of ligand-macromolecule interactions. Significant advances in computational structure prediction of ligand-protein complexes have been made using approaches that include the effects of protein flexibility and incorporate a hierarchy of energy(More)
A new computational method for the in situ generation of small molecules within the binding site of a protein is described. The method has been evaluated using two well-studied systems, dihydrofolate reductase and thymidylate synthase. The method has also been used to guide improvements to inhibitors of HIV-1 protease. One such improvement resulted in a(More)
A microscopic study of functional disorder-order folding transitions coupled to binding is performed for the p27 protein, which derives a kinetic advantage from the intrinsically disordered unbound form on binding with the phosphorylated cyclin A-cyclin-dependent kinase 2 (Cdk2) complex. Hierarchy of structural loss during p27 coupled unfolding and(More)
Monte Carlo simulations of molecular recognition at the consensus binding site of the constant fragment (Fc) of human immunoglobulin G (Ig) protein have been performed to analyze structural and thermodynamic aspects of binding for the 13-residue cyclic peptide DCAWHLGELVWCT. The energy landscape analysis of a hot spot at the intermolecular interface using(More)
Stochastic search algorithms can be used to perform rapid six-dimensional molecular-replacement searches. A molecular-replacement procedure has been developed that uses an evolutionary algorithm to simultaneously optimize the orientation and position of a search model in a unit cell. Here, the performance of this algorithm and its dependence on search model(More)