02994nas a2200193   4500008004100000022001400041245014800055210006900203260007100272300001600343490000800359520219900367100002702566700001602593700002302609700001802632700001902650856013102669       2013                        eng d  a1520-610600aQuantifying the mechanism of phosphate monoester hydrolysis in aqueous solution by evaluating the relevant Ab initio QM/MM free-energy surfaces0 aQuantifying the mechanism of phosphate monoester hydrolysis in a  a1155 16TH ST, NW, WASHINGTON, DC 20036 USAbAMER CHEMICAL SOCcOCT  a12807-128190 v1173 a<p>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 Mg2+ ion because this ion reduces the plc 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).</p>1 aPlotnikoy, Nikolay, V.1 aPrasad, Ram1 aChakrabarty, Suman1 aChu, Zhen, T.1 aWarshel, Arieh  uhttps://library.ncl.res.in/content/quantifying-mechanism-phosphate-monoester-hydrolysis-aqueous-solution-evaluating-relevant-002457nas a2200229   4500008004100000022001400041245010100055210006900156260008000225300001600305490000800321520158800329653003001917653002001947653002301967653002901990100001502019700002302034700002202057700001902079856012902098       2014                        eng d  a0027-842400aModeling gating charge and voltage changes in response to charge separation in membrane proteins0 aModeling gating charge and voltage changes in response to charge  a2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USAbNATL ACAD SCIENCEScAUG  a11353-113580 v1113 a<p>Measurements of voltage changes in response to charge separation within membrane proteins can offer fundamental information on mechanisms of charge transport and displacement processes. A recent example is provided by studies of cytochrome c oxidase. However, the interpretation of the observed voltage changes in terms of the number of charge equivalents and transfer distances is far from being trivial or unique. Using continuum approaches to describe the voltage generation may involve significant uncertainties and reliable microscopic simulations are not yet available. Here, we attempt to solve this problem by using a coarse-grained model of membrane proteins, which includes an explicit description of the membrane, the electrolytes, and the electrodes. The model evaluates the gating charges and the electrode potentials (c.f. measured voltage) upon charge transfer within the protein. The accuracy of the model is evaluated by a comparison of measured voltage changes associated with electron and proton transfer in bacterial photosynthetic reaction centers to those calculated using our coarse-grained model. The calculations reproduce the experimental observations and thus indicate that the method is of general use. Interestingly, it is found that charge-separation processes with different spatial directions (but the same distance perpendicular to the membrane) can give similar observed voltage changes, which indicates that caution should be exercised when using simplified interpretation of the relationship between charge displacement and voltage changes.</p>10abacterial reaction center10aelectrogenicity10amembrane potential10aproton/electron transfer1 aKim, Ilsoo1 aChakrabarty, Suman1 aBrzezinski, Peter1 aWarshel, Arieh  uhttps://library.ncl.res.in/content/modeling-gating-charge-and-voltage-changes-response-charge-separation-membrane-proteins-0