Effects of vibrational energy relaxation and reverse reaction on electron transfer kinetics and fluorescence line shapes in solution

The existing theoretical formulations of electron transfer reactions (ETR) neglect the effects of vibrational energy relaxation (VER) and do not include higher vibrational states in both the reactant and the product surfaces. Both of these aspects can be important for photo-induced electron transfer reactions, particularly for those which are in the Marcus inverted regime. In this article, a theoretical formulation is presented which describes the two aspects. The formalism requires an extension of the hybrid model introduced earlier by Barbara et al. [Science 256, 975 (1992)]. We model a general electron transfer as a two-surface reaction where overlap between the vibrational levels of the two surfaces create multiple, broad reaction windows. The strength and the accessibility of each window is determined by many factors. We find that when VER and reverse transfer are present, the time dependence of the survival probability of the reactant differs significantly (from the case when they are assumed to be absent) for a large range of values of the solvent reorganization energy (λX), quantum mode reorganization energy (λq), electronic coupling constant (Vel) and vibrational energy relaxation rate (kVER). Several interesting results, such as a transient rise in the population of the zeroth vibrational level of the reactant surface, a Kramers (or Grote-Hynes) type recrossing due to back reaction and a pronounced role of the initial Gaussian component of the solvation time correlation function in the dynamics of electron transfer reaction, are observed. Significant dependence of the electron transfer rate on the ultrafast Gaussian component of solvation dynamics is predicted for a range of values of Vel, although dependence on average solvation time can be weak. Another result is that, although VER alters relaxation dynamics in both the product and the reactant surfaces noticeably, the average rate of electron transfer is found to be weakly dependent on kVER for a range of values of Vel; this independence breaks down only at very small values of Vel. In addition, the hybrid model is employed to study the time resolved fluorescence line shape for the electron transfer reactions. It is found that VER can have a significant influence on the fluorescence spectrum. The possibility of vibrational state resolved spectra is investigated

Progress towards a public chemogenomic set for protein kinases and a call for contributions

Protein kinases are highly tractable targets for drug discovery. However, the biological function and therapeutic potential of the majority of the 500+ human protein kinases remains unknown. We have developed physical and virtual collections of small molecule inhibitors, which we call chemogenomic sets, that are designed to inhibit the catalytic function of almost half the human protein kinases. In this manuscript we share our progress towards generation of a comprehensive kinase chemogenomic set (KCGS), release kinome profiling data of a large inhibitor set (Published Kinase Inhibitor Set 2 (PKIS2)), and outline a process through which the community can openly collaborate to create a KCGS that probes the full complement of human protein kinases

Barrierless isomerization dynamics in viscous liquids: decoupling of the reaction rate from the slow frictional forces

Many important chemical and biological reactions do not face a sizable activation barrier in their motion along the reaction coordinate. As a result, these reactions often have time constants in the range of a few hundred femtoseconds (fs) only. The existing theories, on the other hand, assume only the viscous, zero frequency frictional response of the solvent, which is clearly inadequate to describe solvent viscosity effects on such ultrafast reactions. In this article, we present a theory of barrierless chemical reactions that includes the bimodal frictional response of the solvent. The generalized theory is based on a non-Markovian Smoluchowski equation, with a time (t) dependent diffusion coefficient (D(t)) to describe the reactive motion along the reaction surface; the reaction itself is described by a coordinate-dependent sink term. This description is reliable for a harmonic reaction potential energy surface. The time-dependent diffusion coefficient can be obtained from the time-dependent friction by using the known procedure. The calculated rates show that the barrierless reaction rate becomes completely decoupled from slow solvent frictional forces when the rate of the reaction is large. This is particularly true for slow viscous liquids where the fast response of the liquid is vastly separated in a time scale from the slow response. For ultrafast reactions, this theory naturally leads to a fractional viscosity (η) dependence of the rate (k ~ η-α), with the value of the exponent a being close to zero at large solvent viscosities. The theory predicts excitation wavelength and temperature dependence in agreement with experiments. The results of the theory have been used to analyze and understand the experimental results of isomerization in rhodopsin, isorhodopsin, crystal violet, and several other cases

Barrierless Isomerization Dynamics in Viscous Liquids: Decoupling of the Reaction Rate from the Slow Frictional Forces

Many important chemical and biological reactions do not face a sizable activation barrier in their motion along the reaction coordinate. As a result, these reactions often have time constants in the range of a few hundred femtoseconds (fs) only. The existing theories, on the other hand, assume only the viscous, zero frequency frictional response of the solvent, which is clearly inadequate to describe solvent viscosity effects on such ultrafast reactions. In this article, we present a theory of barrierless chemical reactions that includes the bimodal frictional response of the solvent. The generalized theory is based on a non-Markovian Smoluchowski equation, with a time (t) dependent diffusion coefficient (D(t)) to describe the reactive motion along the reaction surface; the reaction itself is described by a coordinate-dependent sink term. This description is reliable for a harmonic reaction potential energy surface. The time-dependent diffusion coefficient can be obtained from the time-dependent friction by using the known procedure. The calculated rates show that the barrierless reaction rate becomes completely decoupled from slow solvent frictional forces when the rate of the reaction is large. This is particularly true for slow viscous liquids where the fast response of the liquid is vastly separated in a time scale from the slow response. For ultrafast reactions, this theory naturally leads to a fractional viscosity (eta) dependence of the rate (k similar to eta(-alpha)), with the value of the exponent ct being close to zero at large solvent viscosities. The theory predicts excitation wavelength and temperature dependence in agreement with experiments. The results of the theory have been used to analyze and understand the experimental results of isomerization in rhodopsin, isorhodopsin, crystal violet, and several other cases

Structure-Based Design of Highly Selective Inhibitors of the CREB Binding Protein Bromodomain

Chemical probes are required for preclinical target validation to interrogate novel biological targets and pathways. Selective inhibitors of the CREB binding protein (CREBBP)/EP300 bromodomains are required to facilitate the elucidation of biology associated with these important epigenetic targets. Medicinal chemistry optimization that paid particular attention to physiochemical properties delivered chemical probes with desirable potency, selectivity, and permeability attributes. An important feature of the optimization process was the successful application of rational structure-based drug design to address bromodomain selectivity issues (particularly against the structurally related BRD4 protein)

Tetrahydrocarbazole-Based Serotonin Reuptake Inhibitor/Dopamine D2 Partial Agonists for the Potential Treatment of Schizophrenia

A 5-fluoro-tetrahydrocarbazole serotonin reuptake inhibitor (SRI) building block was combined with a variety of linkers and dopamine D2 receptor ligands in an attempt to identify potent D2 partial agonist/SRI molecules for treatment of schizophrenia. This approach has the potential to treat a broader range of symptoms compared to existing therapies. Selected compounds in this series demonstrate high affinity for both targets and D2 partial agonism in cell-based and in vivo assays