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Molecular dynamics simulations have become an important tool for the study of structures, dynamics, and functions of biomolecules. Time scales and force field accuracy are key factors for the reliability of these simulations. With the advancement of computational platforms and simulation technologies, all-atom simulations of proteins in explicitly represented aqueous solutions can reach as long as milliseconds. However, there are indications of minor force field flaws in literature. In this work we present our observations on force field accuracy under uncommon conditions. We performed molecular dynamics simulations of BBL refolding in aqueous solutions of acidic pH and high salt concentrations (up to 6 M) with the AMBER99SB-ILDN force field for a microsecond time scale. The reliability of the simulations relies on the accuracy of the physical models of protein, water, and ions. Our simulations show the same trend as experiments: higher salt concentration facilities refolding. However, we have observed the presence of β-sheet in the native helical region as well as α-helix and β-sheet in the native loop region. Some of the nonnative secondary structures are even more stable than native helices. Aside from the secondary structure issue under the uncommon conditions, we have found that the rigidity of glycine dihedral angles in the loop region leads to low root-mean-square deviations but large topological differences from the native structure. Whether this is due to a force field deficiency or not needs further investigations. Recently developed ion parameters exhibit evident liquid features even in the 6 M LiCl solution. However, cation-anion interactions in TIP3P water still seem too strong, leading to high fractions of contact ion pairs. We do not find any specific ion-binding motif, thus we conclude that the effect of salt is a nonspecific electrostatic screening in our simulations. Our observations on the AMBER force field performance under acidic conditions and high salt concentrations show that simulations under extreme conditions can provide informative tests of physical models.

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Derivatives of geraniol are versatile synthetic intermediates that are useful for synthesizing a variety of terpenoid natural products; however, the results presented herein show that subtle differences in the structures of functionalized geranyl chlorides can significantly impact their abilities to function as effective electrophiles in synthetic reactions. A series of focused kinetics experiments identify specific structure-activity relationships that illustrate the importance not only of steric bulk, but also of electronic effects from distant regions of the molecules that contribute to their overall levels of reactivity. Computational modeling suggests that destabilization of the reactant by filled-filled orbital mixing events in some, but not all, conformations may be a critical contributor to these important electronic effects.

The diffusion map is a dimensionality reduction method. The reduction coordinates are associated with the leading eigenfunctions of the backward Fokker–Planck operator, providing a dynamic meaning for these coordinates. One of the key factors that affect the accuracy of diffusion map embedding is the dynamic measure implemented in the Gaussian kernel. A common practice in diffusion map study of molecular systems is to approximate dynamic proximity with RMSD (root-mean-square deviation). In this paper, we present a hybrid geometry-energy based kernel. Since high energy-barriers may exist between geometrically similar conformations, taking both RMSD and energy difference into account in the kernel can better describe conformational transitions between neighboring conformations and lead to accurate embedding. We applied our diffusion map method to the β-hairpin of the B1 domain of streptococcal protein G and to Trp-cage. Our results in β-hairpin show that the diffusion map embedding achieves better results with the hybrid kernel than that with the RMSD-based kernel in terms of free energy landscape characterization and a new correlation measure between the cluster center Euclidean distances in the reduced-dimension space and the reciprocals of the total net flow between these clusters. In addition, our diffusion map analysis of the ultralong molecular dynamics trajectory of Trp-cage has provided a unified view of its folding mechanism. These promising results demonstrate the effectiveness of our diffusion map approach in the analysis of the dynamics and thermodynamics of molecular systems. The hybrid geometry-energy criterion could be also useful as a general dynamic measure for other purposes.