Cyclization and selected backbone N-methylations are found to be often necessary but not sufficient conditions for peptidic drugs to have a good bioavailability. Thus, the design of cyclic peptides with good passive membrane permeability and good solubility remains a challenge. The backbone scaffold of a recently published series of cyclic decapeptides with six selected backbone N-methylations was designed to favor the adoption of a closed conformation with β-turns and four transannular hydrogen bonds. Although this conformation was indeed adopted by the peptides as determined by NMR measurements, substantial differences in the membrane permeability were observed. In this work, we aim to rationalize the impact of discrete side chain modifications on membrane permeability for six of these cyclic decapeptides. The thermodynamic and kinetic properties were investigated using molecular dynamics simulations and Markov state modeling in water and chloroform. The study highlights the influence that side-chain modifications can have on the backbone conformation. Peptides with a d-proline in the β-turns were more likely to adopt, even in water, the closed conformation with transannular hydrogen bonds, which facilitates transition through the membrane. The population of the closed conformation in water was found to correlate positively with PAMPA log P e.

Alchemical free energy calculations typically rely on intermediate states to bridge between the relevant phase spaces of the two end states. These intermediate states are usually created by mixing the energies or parameters of the end states according to a coupling parameter λ. The choice of the procedure has a strong impact on the energy calculations considering five benchmark systems. The first two systems (charge inversion and cavity creation in a dipolar solvent) demonstrate the use of λ-EDS as an alternative coupling scheme in the context of thermodynamic integration (TI). The three other systems (change of bond length, change of dihedral angles, and cavity creation in water) investigate the efficiency and optimal choice of parameters in the context of free energy perturbation (FEP) and Bennett's acceptance ratio (BAR). It is shown that λ-EDS allows larger steps along the alchemical pathway than conventional intermediate states.

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An overarching mathematical framework is proposed to describe entire mineral particle precipitation processes, including multiple polymorphic forms and ranges of temperatures. While existing models portray individual physical phenomena, the presented approach incorporates a diverse set of the physical phenomena simultaneously within a single mathematical description. The liquid and solid phase dynamics interact through coupling an aqueous ionic equilibrium-chemistry model with a set of population balance equations and a mixing model. Including the particle physical phenomena, nucleation, growth, dissolution, and aggregation together within a single framework allows for the exploration of nonintuitive and nontrivial coupling effects. To validate the proposed framework, the CaCO3 system and results described within Ogino, T.; Suzuki, T.; Sawada, K. Geochim. Cosmochim. Acta 1987, 51, 2757–2767 were utilized. The proposed framework captures general trends and timescales, even while being constructed of relatively basic physical models with approximations and known uncertainties. Interpolymorph coupling effects, which were found to be important in the validation system’s evolution, and dynamics within each polymorph’s particle size distribution are captured by the framework.