Absolute binding free energy calculations of CBClip host-guest systems in the SAMPL5 blind challenge.

Herein, we report the absolute binding free energy calculations of CBClip complexes in the SAMPL5 blind challenge. Initial conformations of CBClip complexes were obtained using docking and molecular dynamics simulations. Free energy calculations were performed using thermodynamic integration (TI) with soft-core potentials and Bennett's acceptance ratio (BAR) method based on a serial insertion scheme. We compared the results obtained with TI simulations with soft-core potentials and Hamiltonian replica exchange simulations with the serial insertion method combined with the BAR method. The results show that the difference between the two methods can be mainly attributed to the van der Waals free energies, suggesting that either the simulations used for TI or the simulations used for BAR, or both are not fully converged and the two sets of simulations may have sampled difference phase space regions. The penalty scores of force field parameters of the 10 guest molecules provided by CHARMM Generalized Force Field can be an indicator of the accuracy of binding free energy calculations. Among our submissions, the combination of docking and TI performed best, which yielded the root mean square deviation of 2.94 kcal/mol and an average unsigned error of 3.41 kcal/mol for the ten guest molecules. These values were best overall among all participants. However, our submissions had little correlation with experiments.

Unusual Aspects of Charge Regulation in Flexible Weak Polyelectrolytes.

This article reviews the state of the art of the studies on charge regulation (CR) effects in flexible weak polyelectrolytes (FWPE). The characteristic of FWPE is the strong coupling of ionization and conformational degrees of freedom. After introducing the necessary fundamental concepts, some unconventional aspects of the the physical chemistry of FWPE are discussed. These aspects are: (i) the extension of statistical mechanics techniques to include ionization equilibria and, in particular, the use of the recently proposed Site Binding-Rotational Isomeric State (SBRIS) model, which allows the calculation of ionization and conformational properties on the same foot; (ii) the recent progresses in the inclusion of proton equilibria in computer simulations; (iii) the possibility of mechanically induced CR in the stretching of FWPE; (iv) the non-trivial adsorption of FWPE on ionized surfaces with the same charge sign as the PE (the so-called "wrong side" of the isoelectric point); (v) the influence of macromolecular crowding on CR.

Adsorption of flexible proteins in the 'wrong side' of the isoelectric point: Casein macropeptide as a model system.

We analyze the conditions of the adsorption of a flexible peptide onto a charged substrate in the 'wrong side' of the isoelectric point (WSIP), i.e. when surface and peptide charges have the same sign. As a model system, we focus on the casein macropeptide (CMP), both in the aglycosylated (aCMP) and fully glycosydated (gCMP) forms. We model the substrate as a uniformly charged plane while CMP is treated as a bead-and-spring model including electrostatic interactions, excluded volume effects and acid/base equilibria. Adsorption coverage, aminoacid charges and concentration profiles are computed by means of Monte Carlo simulations at fixed pH and salt concentration. We conclude that for different reasons the CMP can be adsorbed to both positively and negatively charged surfaces in the WSIP. For negatively charged surfaces, WSIP adsorption is due to the patchy distribution of charges: the peptide is attached to the surface by the positively charged end of the chain, while the repulsion of the surface for the negatively charged tail is screened by the small ions of the added salt. This effect increases with salt concentration. Conversely, a positively charged substrate induces strong charge regulation of the peptide: the acidic groups are deprotonated, and the peptide becomes negatively charged. This effect is stronger at low salt concentrations and it is more intense for gCMP than for aCMP, due to the presence of the additional sialic groups in gCMP.

Understanding and Controlling Food Protein Structure and Function in Foods: Perspectives from Experiments and Computer Simulations.

The structure and interactions of proteins play a critical role in determining the quality attributes of many foods, beverages, and pharmaceutical products. Incorporating a multiscale understanding of the structure-function relationships of proteins can provide greater insight into, and control of, the relevant processes at play. Combining data from experimental measurements, human sensory panels, and computer simulations through machine learning allows the construction of statistical models relating nanoscale properties of proteins to the physicochemical properties, physiological outcomes, and tastes of foods. This review highlights several examples of advanced computer simulations at molecular, mesoscale, and multiscale levels that shed light on the mechanisms at play in foods, thereby facilitating their control. It includes a practical simulation toolbox for those new to in silico modeling.

Computational scheme for pH-dependent binding free energy calculation with explicit solvent.

We present a computational scheme to compute the pH-dependence of binding free energy with explicit solvent. Despite the importance of pH, the effect of pH has been generally neglected in binding free energy calculations because of a lack of accurate methods to model it. To address this limitation, we use a constant-pH methodology to obtain a true ensemble of multiple protonation states of a titratable system at a given pH and analyze the ensemble using the Bennett acceptance ratio (BAR) method. The constant pH method is based on the combination of enveloping distribution sampling (EDS) with the Hamiltonian replica exchange method (HREM), which yields an accurate semi-grand canonical ensemble of a titratable system. By considering the free energy change of constraining multiple protonation states to a single state or releasing a single protonation state to multiple states, the pH dependent binding free energy profile can be obtained. We perform benchmark simulations of a host-guest system: cucurbit[7]uril (CB[7]) and benzimidazole (BZ). BZ experiences a large pKa shift upon complex formation. The pH-dependent binding free energy profiles of the benchmark system are obtained with three different long-range interaction calculation schemes: a cutoff, the particle mesh Ewald (PME), and the isotropic periodic sum (IPS) method. Our scheme captures the pH-dependent behavior of binding free energy successfully. Absolute binding free energy values obtained with the PME and IPS methods are consistent, while cutoff method results are off by 2 kcal mol(-1) . We also discuss the characteristics of three long-range interaction calculation methods for constant-pH simulations.