Enhanced Conformational Sampling of Nanobody CDR H3 Loop by Generalized Replica-Exchange with Solute Tempering

The variable domains of heavy-chain antibodies, known as nanobodies, are potential substitutes for IgG antibodies. They have similar affinities to antigens as antibodies, but are more heat resistant. Their small size allows us to exploit computational approaches for structural modeling or design. Here, we investigate the applicability of an enhanced sampling method, a generalized replica-exchange with solute tempering (gREST) for sampling CDR-H3 loop structures of nanobodies. In the conventional replica-exchange methods, temperatures of only a whole system or scaling parameters of a solute molecule are selected for temperature or parameter exchange. In gREST, we can flexibly select a part of a solute molecule and a part of the potential energy terms as a parameter exchange region. We selected the CDR-H3 loop and investigated which potential energy term should be selected for the efficient sampling of the loop structures. We found that the gREST with dihedral terms can explore a global conformational space, but the relaxation to the global equilibrium is slow. On the other hand, gREST with all the potential energy terms can sample the equilibrium distribution, but the structural exploration is slower than with dihedral terms. The lessons learned from this study can be applied to future studies of loop modeling.

ON INFLUENCE OF H/D EXCHANGE ON SOLVENT ISOTOPE EFFECTS IN THERMODYNAMIC (ENTHALPIC) CHARACTERISTICS OF SOLVATION OF PROTON-DONATING NON-ELECTROLYTES

Some features of the solvent H/D-isotope effect method are discussed in the frame of development of ideas about the solvation mechanism including the structural and thermodynamic characteristics concept being proposed by G.A. Krestov and its followers. We have found it necessary to debate the possibility of employing the H2O-by-D2O isotope substitution for thermodynamic studying of binary aqueous systems containing a proton-donating organic non-electrolyte. In this regard, the two main aspects of the problem are discussed: (i) how the H-D exchange affects the thermodynamic (enthalpic) solvent isotope effects and (ii) how such effects dependent on the partial or complete pre-deuteration of a solute molecule. All potentially exchangeable protons (of N-H, O-H,) in heavy water are replaced by deuterons, but the fast exchange of D between D2O and the C-H (in methyl and methylen groups) does not occur. Herewith the extent to which proton-donor sites in complex molecules are stabilized by intramolecular hydrogen bonding remains uncertain, making it difficult to assess details of H-D exchange mechanisms in the hydration process. It is important to note that the H-D-isotope exchange is accompanied by changes in the molecular composition both the solute and solvent (due to forming HDO) in the nearest environment. This affects the thermodynamic (mole-additive) parameters of solvation process in heavy water as well as the corresponding isotope effects. The problem can be partly overcome by using the deuterium-substitution in a solute molecule. In this case, the molar mass of each solution component does not change but we should not forget here on the effect of secondary H/D isotope substitution in the solute. From a purely thermodynamic view, we can focus only on the analysis of H/D isotope effects in characteristics of its sublimation or vaporization. Herewith H- and D-bonded systems have the same distinctions in the (zero-point) vibration energy as in individual components. It because the specified isotope effects can be rather directly related to the condensed-phase partition functions which may be written down under the assumption of isotope-independent potential energy surface (within the precision of Born-Oppenheimer “adiabatic” approximation).

X-ray Raman scattering: a new in situ probe of molecular structure during nucleation and crystallization from liquid solutions

X-ray Raman scattering (XRS) has been used for in situ probing of solute molecule speciation in solution during cooling crystallization.

An Activity Coefficient Model Based on the Hydration for Electrolyte Solutions

This paper proposes a hypothesis of hydration. It assumes that the solute in the electrolyte solution exists as molecules, and each solute molecule is surrounded by h water molecules. On this basis, this paper deduces the activity coefficient formulas, and the model is applied to binary electrolyte solutions at room and elevated temperatures.

Using the Quantitative Structure-Property Relationship to Correlate the Infinite Dilution Activity Coefficients of Organic Compounds in 1-Ethyl-3-Methylimidazolium Diethylphosphate

On the basis of the quantitative structure-property relationship (QSPR) method and the quantum chemical descriptors including molecular van der Waals volume (Vmc), dipole moments (μ), the most negative formal charge in solute molecule (q-), and the most positive formal charge on a hydrogen atom in solute molecule (q+) of organic compounds, the values of activity coefficients at infinite dilution, , for 16 solutes in ionic liquid 1-ethyl-3-methylimidazolium diethylphosphate ([EMIM][DEP]) at 323.15 K were correlated with the descriptors. The result showed that the QSPR model had a good correlation and could successfully describe . The quantitative relationship between organic molecular structure and in [EMIM][DEP] was obtained and the correlation parameters were analyzed to understand the interactions that affect activity coefficients at infinite dilution.