to be used for computations of large systems. In addition, the report includes the description of a computational machinery for nonlinear optical spectroscopy through an interface to the QM/MM package Cobramm. Further, a module to run molecular dynamics simulations is added and two surface hopping algorithms are included to enable nonadiabatic calculations. Finally, we report on the subject of improvements with respects to alternative file options and parallelization.

Protein allosteric pathways are investigated in the imidazole glycerol phosphate synthase heterodimer in an effort to elucidate how the effector (PRFAR,formimino]-5-aminoimidazole-4-carboxamide ribonucleotide) activates glutaminase catalysis at a distance of 25 Å from the glutamine-binding site. We apply solution NMR techniques and community analysis of dynamical networks, based on mutual information of correlated protein motions in the active and inactive enzymes. We find evidence that the allosteric pathways in the PRFAR bound enzyme involve conserved residues that correlate motion of the PRFAR binding loop to motion at the protein-protein interface, and ultimately at the glutaminase active site. The imidazole glycerol phosphate synthase bienzyme is an important branch point for the histidine and nucleotide biosynthetic pathways and represents a potential therapeutic target against microbes. The proposed allosteric mechanism and the underlying allosteric pathways provide fundamental insights for the design of new allosteric drugs and/or alternative herbicides.glutamine hydrolysis | protein networks | generalized correlation analysis | network theory A llostery is a fundamental property that allows for the regulation of function and dynamic adaptability of enzymes and proteins. Allosteric enzymes contain at least two distant binding sites, including the active site responsible for catalytic activity, which binds the substrate, and the allosteric site, which binds the effector and initiates the allosteric signal propagation to the active site. In V-type systems, substrate binding is not affected by the presence of the effector but if the effector is not bound, the allosteric protein is usually catalytically inactive (or poorly active), indicating that the effector binding is coupled to the kinetic and/or thermodynamic parameters of the biochemical reaction in the active site. Allosteric information transfer can range from large, enthalpically driven conformational changes to purely entropically driven motions or a combination of both enthalpic and entropic effects, but in each case the kinetic parameters of the catalyzed reaction at the substrate binding site are altered. At the heart of allosterism there is intramolecular thermodynamic coupling over long distances (>10 Å), between the active and allosteric sites. An important challenge for fundamental studies is the elucidation of the allosteric pathways that connect the two ligand-binding sites.In this work, we combine community network analysis based on molecular dynamics (MD) simulations and NMR studies of protein motion based on relaxation dispersion techniques and chemical shift titrations experiments to provide an atomistic description of allostery in the V-type allosteric enzyme imidazole glycerol phosphate synthase (IGPS) from the thermophile Thermotoga maritima (Fig. 1). IGPS is a tightly associated heterodimeric enzyme in which each monomer enzyme catalyzes a different reaction (1-3). The 23 kDa HisH enzyme is a member of the glutamine amidotransferas...

Allosteric regulation plays an important role in many biological processes, such as signal transduction, transcriptional regulation, and metabolism. Allostery is rooted in the fundamental physical properties of macromolecular systems, but its underlying mechanisms are still poorly understood. A collection of contributions to a recent interdisciplinary CECAM (Center Européen de Calcul Atomique et Moléculaire) workshop is used hereto provide an overview of the progress and remaining limitations in the understanding of the mechanistic foundations of allostery gained from computational and experimental analyses of real protein systems and model systems. The main conceptual frameworks instrumental in driving the field are discussed. We illustrate the role of these frameworks in illuminating molecular mechanisms and explaining cellular processes, and describe some of their promising practical applications in engineering molecular sensors and informing drug design efforts.