Protonated state

In molecular mechanics and molecular dynamics studies of proteins, assig-ment of standard, non-dynamical ionization states of protein titratable groups is a common practice. This assumption seems to be well justified because proton exchange times between protein and solution usually far exceed the time range of the MD simulations. We investigated to what extent the assumed protonation state of a protein influences its molecular dynamics trajectory, and how often our titration algorithm predicted ionization states identical to those imposed on the groups, when applied to a set of structures derived from a molecular dynamics trajectory [34]. As a model we took the bovine... 

Continuum electrostatic approaches based on the Poisson equation have been used to address a wide variety of problems in biology. One particularly useful application is in the determination of the protonation state of titratable groups in proteins [46]. For... 

FIGURE 10.22 The reaction cycle of bacteriorhodopsin. The intermediate states are indicated by letters, with subscripts to indicate the absorption maxima of the states. Also indicated for each state is the configuration of the retinal chromophore (all-tram or 13-cas) and the protonation state of the Schiff base (C=N or C=N H). 

Scientists are trying to synthesize elements with more than 114 protons. State the expected atomic number of... 

The potency of the inhibitors is affected by the pH. Changes in pH affect the protonation state of the guanidine. In conditions of low pH, such as in ischemia-reperfusion, some dtugs such as cariporide work more efficiently because they are on average more positively charged. 

Comparison of solution pH with the pKa of a side chain informs about the protonation state. A unique pKa, termed the standard or model pKa, can be experimentally determined for each ionizable side chain in solution when it is incorporated in a model compound, often a blocked amino acid residue [73] (Table 10-1). In a protein environment, however, the pKa value of an ionizable side chain can substantially deviate from the standard value, due to desolvation effects, hydrogen bonding, charge-charge, charge-dipole, and other electrostatic interactions with the... 

Constant pH Molecular Dynamics Based on Discrete Protonation States... 

In recent years, a class of methods has been developed for molecular dynamics simulations to be performed with an external pH parameter, like temperature or pressure [18, 43, 44, 70], These methods treat the solution as an infinite proton bath, and are thus referred to as constant pH molecular dynamics (PHMD). In PHMD, conformational dynamics of a protein is sampled simultaneously with the protonation states as a function of pH. As a result, protein dielectric response to the... 

The discrete protonation states methods employing implicit solvent models in both MD and MC steps have significantly lower computational cost. Dlugosz and... 

The discrete protonation states methods have been tested in pKa calculations for several small molecules and peptides, including succinic acid [4, 25], acetic acid [93], a heptapeptide derived from ovomucoid third domain [27], and decalysine [61], However, these methods have sofar been tested on only one protein, the hen egg lysozyme [16, 61, 71], While the method using explicit solvent for both MD and MC sampling did not give quantitative agreement with experiment due to convergence difficulty [16], the results using a GB model [71] and the mixed PB/explicit... 

In an early work by Mertz and Pettitt, an open system was devised, in which an extended variable, representing the extent of protonation, was used to couple the system to a chemical potential reservoir [67], This method was demonstrated in the simulation of the acid-base reaction of acetic acid with water [67], Recently, PHMD methods based on continuous protonation states have been developed, in which a set of continuous titration coordinates, A, bound between 0 and 1, is propagated simultaneously with the conformational degrees of freedom in explicit or continuum solvent MD simulations. In the acidostat method developed by Borjesson and Hiinenberger for explicit solvent simulations [13], A. is relaxed towards the equilibrium value via a first-order coupling scheme in analogy to Berendsen s thermostat [10]. However, the theoretical basis for the equilibrium condition used in the derivation seems unclear [3], A test using the pKa calculation for several small amines did not yield HH titration behavior [13],... 

The titration coordinates evolve along with the dynamics of the conformational degrees of freedom, r, in simulations with GB implicit solvent models [37, 57], An extended Hamiltonian formalism, in analogy to the A dynamics technique developed for free energy calculations [50], is used to propagate the titration coordinates. The deprotonated and protonated states are those, for which the A value is approximately 1 or 0 (end-point states), respectively. Thus, in contrast to the acidostat method, where A represents the extent of deprotonation, is estimated from the relative occupancy of the states with A 1 (see later discussions). The extended Hamiltonian in the CPHMD method is a sum of the following terms [42],... 

Bashford D (2004) Macroscopic electrostatic models for protonation states in proteins. Front Bioscience 9 1082-1099. 

Stem HA (2007) Molecular simulation with variable protonation states at constant pH. J Chem Phys 126 164112. 

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