ABSTRACT
We develop ∂-HylleraasMD (∂-HyMD), a fully end-to-end differentiable molecular dynamics software based on the Hamiltonian hybrid particle-field formalism, and use it to establish a protocol for automated optimization of force field parameters. ∂-HyMD is templated on the recently released HylleraaasMD software, while using the JAX autodiff framework as the main engine for the differentiable dynamics. ∂-HyMD exploits an embarrassingly parallel optimization algorithm by spawning independent simulations, whose trajectories are simultaneously processed by reverse mode automatic differentiation to calculate the gradient of the loss function, which is in turn used for iterative optimization of the force-field parameters. We show that parallel organization facilitates the convergence of the minimization procedure, avoiding the known memory and numerical stability issues of differentiable molecular dynamics approaches. We showcase the effectiveness of our implementation by producing a library of force field parameters for standard phospholipids, with either zwitterionic or anionic heads and with saturated or unsaturated tails. Compared to the all-atom reference, the force field obtained by ∂-HyMD yields better density profiles than the parameters derived from previously utilized gradient-free optimization procedures. Moreover, ∂-HyMD models can predict with good accuracy properties not included in the learning objective, such as lateral pressure profiles, and are transferable to other systems, including triglycerides.
ABSTRACT
We report a physicochemical investigation of the lipid transport properties of model lipid membranes in the presence of the antimicrobial peptide indolicidin through comparisons of experimental SANS/SAXS scattering techniques to fully atomistic molecular dynamics simulations. In agreement with the experiment, we show that upon peripheral binding of the peptides, even at low concentrations, lipid flip-flop dynamics is greatly accelerated. Computer modeling elucidates the interplay between structural changes and lipid dynamics induced by peptides and proposes a mechanism for the mode of action of antimicrobial peptides, assessing the major role of entropy for the catalysis of the flipping events. The mechanism introduced here is universal for all peptides with preferential peripheral binding to the membrane as it does not depend on the specific amino acid sequence.
Subject(s)
Lipid Bilayers , Lipid Bilayers/chemistry , Scattering, Small Angle , X-Ray Diffraction , Amino Acid Sequence , Biological TransportABSTRACT
Understanding the interactions and the solvent effects on the distribution of several species in equilibrium and how it can influence the 1H-NMR properties, spectroscopy (UV-vis absorption), and the acid-base equilibria can be especially challenging. This is the case of a bis-bidentate bridging ligand bis(2-pyridyl)-benzo-bis(imidazole), where the two pyridyl and four imidazolyl nitrogen atoms can be protonated in different ways, depending on the solvent, generating many isomeric/tautomeric species. Herein, we report a combined theoretical-experimental approach based on a sequential quantum mechanics/molecular mechanics procedure that was successfully applied to describe in detail the acid-base characterization and its effects on the electronic properties of such a molecule in solution. The calculated free-energies allowed the identification of the main species present in solution as a function of the solvent polarity, and its effects on the magnetic shielding of protons (1H-NMR chemical shifts), the UV-vis absorption spectra, and the acid-base equilibrium constants (pKas) in aqueous solution. Three acid-base equilibrium constants were experimentally/theoretically determined (pKa1 = 1.3/1.2, pKa2 = 2.1/2.2 and pKa5 = 10.1/11.3) involving mono-deprotonated and mono-protonated cis and trans species. Interestingly, other processes with pKa3 = 3.7 and pKa4 = 6.0 were also experimentally determined and assigned to the protonation and deprotonation of dimeric species. The dimerization of the most stable neutral species was investigated by Monte Carlo simulations and its electronic effects were considered for the elucidation of the UV-vis absorption bands, revealing transitions mainly with the charge-transfer characteristic and involving both the monomeric species and the dimeric species. The good matching of the theoretical and experimental results provides an atomistic insight into the solvent effects on the electronic properties of this bis-bidentate bridging ligand.
