Quantifying the mechanism of phosphate monoester hydrolysis in aqueous solution by evaluating the relevant ab initio QM/MM free-energy surfaces.

Understanding the nature of the free-energy surfaces for phosphate hydrolysis is a prerequisite for understanding the corresponding key chemical reactions in biology. Here, the challenge has been to move to careful ab initio QM/MM (QM(ai)/MM) free-energy calculations, where obtaining converging results is very demanding and computationally expensive. This work describes such calculations, focusing on the free-energy surface for the hydrolysis of phosphate monoesters, paying special attention to the comparison between the one water (1W) and two water (2W) paths for the proton-transfer (PT) step. This issue has been explored before by energy minimization with implicit solvent models and by nonsystematic QM/MM energy minimization, as well as by nonsystematic free-energy mapping. However, no study has provided the needed reliable 2D (3D) surfaces that are necessary for reaching concrete conclusions. Here we report a systematic evaluation of the 2D (3D) free-energy maps for several relevant systems, comparing the results of QM(ai)/MM and QM(ai)/implicit solvent surfaces, and provide an advanced description of the relevant energetics. It is found that the 1W path for the hydrolysis of the methyl diphosphate (MDP) trianion is 6-9 kcal/mol higher than that the 2W path. This difference becomes slightly larger in the presence of the Mg(2+) ion because this ion reduces the pKa of the conjugated acid form of the phosphate oxygen that accepts the proton. Interestingly, the BLYP approach (which has been used extensively in some studies) gives a much smaller difference between the 1W and 2W activation barriers. At any rate, it is worth pointing out that the 2W transition state for the PT is not much higher that the common plateau that serves as the starting point of both the 1W and 2W PT paths. Thus, the calculated catalytic effects of proteins based on the 2W PT mechanistic model are not expected to be different from the catalytic effects predicted using the 1W PT mechanistic model, which was calibrated on the observed barrier in solution and in which the TS charge distribution was similar to the that of the plateau (as was done in all of our previous EVB studies).

Addressing open questions about phosphate hydrolysis pathways by careful free energy mapping.

The nature and mechanism of phosphate hydrolysis reactions are of great interest in view of the crucial role of these reactions in key biological processes. Although it is becoming clearer that the ultimate way of resolving mechanistic controversies must involve reliable theoretical studies, it is not widely realized that such studies cannot be performed at present by using most existing automated ways and that only careful systematic studies can lead to meaningful conclusions. The present work clarifies the above point by considering the hydrolysis of phosphate monoesters. The clarification starts by defining the actual issues that should be addressed in careful studies and by highlighting the problems with studies that ignore the need for unique mechanistic definitions (e.g., works that confuse associative and dissociative pathways). We then focus on the analysis of the proton transfer (PT) pathways in phosphate hydrolysis and on recent suggestions that PT involves more than one water molecule. Here we point out that most of the studies that found a proton transfer through several water molecules have not involved a sufficient systematic search of the relevant reaction coordinates. This includes both energy minimization approaches as well as a recent metadynamics (MTD) simulation study. To illustrate the crucial need of exploring the potential surfaces reliably, rather than relying on automated approaches, we present here a very careful study of the free energy landscape along a 3D reaction coordinate (RC) exploring both the standard 2D RC, comprised of the attacking and leaving group reaction coordinates, as well as of the proton transfer (PT) coordinate. Our study points out that QM/MM minimization or MTD studies that concluded that the hydrolysis of phosphate monoesters involves a PT through several water molecules, have not explored carefully the single water (1W) path (that involves a direct PT form the attacking water molecule to the phosphate oxygen). Furthermore, we identified the most likely reason for the difficulty in finding the 1W path by QM/MM minimization methods, as well as by the current MTD simulations. We also discuss the problems with current studies that challenge the phosphate as a base mechanism and emphasize that all recent studies found associative/concerted paths (although many have not realized the meaning of their results). Finally, although we clearly do not have the last word about the 1W versus 2W paths we believe that we illustrated that the crucial mechanistic problems with alternative pathways should not be resolved by just running black box search approaches.

Explaining the differential solubility of flue gas components in ionic liquids from first-principle calculations.

Flue gas is greatly responsible for acid rain formation and global warming. New generation ionic liquids (ILs) have potential in controlling the flue gas emissions, as they acquire high absorptivity for the component gases SO(2), CO(2), etc. The association of the IL-gas interactions to the absorptivity of gas molecules in ILs is, however, poorly understood. In this paper, we present a molecular level description of the interactions of ILs with SO(2), CO(2), and N(2) and show its implications to the differential gas solubility. Our results indicate that the IL anion-gas interactions play a key role in deciding the gas solubility in ILs, particularly for polar gases such as SO(2). On the other hand, regular solution assumption applies to N(2) solubility. In accordance with the previous theoretical and experimental findings, our results also imply that the IL anions dominate the interactions with gas molecules while the cations play a secondary role and the underlying fluid structures of the ILs remain unperturbed by the addition of gas molecules.