Connection atoms are proposed as an alternative to link atoms in semiempirical hybrid calculations that divide a system at a C−C single bond into a quantum mechanical (QM) and a molecular mechanical (MM) region. A connection atom interacts with the other QM atoms as a specially parametrized QM atom, and with the other MM atoms as a standard carbon MM atom. Detailed definitions of these interactions are given for three QM/MM coupling models (A mechanical embedding, B/C electronic embedding without/with MM polarization). Semiempirical connection atom parameters are derived for three standard methods (MNDO, AM1, PM3) such that the adjusted connection atoms closely reproduce the geometrical and electronic properties of methyl groups. The corresponding deviations are generally smaller than the intrinsic errors of these methods. QM/MM test calculations on proton affinities confirm the usefulness of the adjusted connection atoms, particularly in coupling model B. Connection atoms are conceptually superior to link atoms in that they do not introduce extra centers and thus lead to well-defined potential surfaces. In addition, they allow an improved semiempirical description of the QM/MM interactions

The effect of motional averaging when relating structural properties inferred from nuclear magnetic resonance (NMR) experiments to molecular dynamics simulations of peptides is considered. In particular, the effect of changing populations of conformations, the extent of sampling, and the sampling frequency on the estimation of nuclear Overhauser effect (NOE) inter-proton distances, vicinal 3 J-coupling constants, and chemical shifts are investigated. The analysis is based on 50-ns simulations of a ␤-heptapeptide in methanol at 298 K, 340 K, 350 K, and 360 K. This peptide undergoes reversible folding and samples a significant proportion of the available conformational space during the simulations, with at 298 K being predominantly folded and at 360 K being predominantly unfolded. The work highlights the fact that when motional averaging is included, NMR data has only limited capacity to distinguish between a single fully folded peptide conformation and various mixtures of folded and unfolded conformations. Proteins 1999;36:542-555.1999 Wiley-Liss, Inc.

Several coupling models and link atom options are investigated for combined quantum-chemical and classical approaches. Ab initio, density functional, and semiempirical methods are used for the quantum-chemical region, whereas the classical region is described by the AMBER force field. Numerical results are reported for the proton affinities of alcohols and ethers. Recommendations for link atoms are given based on these results and theoretical analysis

The effect of motional averaging when relating structural properties inferred from nuclear magnetic resonance (NMR) experiments to molecular dynamics simulations of peptides is considered. In particular, the effect of changing populations of conformations, the extent of sampling, and the sampling frequency on the estimation of nuclear Overhauser effect (NOE) inter-proton distances, vicinal (3)J-coupling constants, and chemical shifts are investigated. The analysis is based on 50-ns simulations of a beta-heptapeptide in methanol at 298 K, 340 K, 350 K, and 360 K. This peptide undergoes reversible folding and samples a significant proportion of the available conformational space during the simulations, with at 298 K being predominantly folded and at 360 K being predominantly unfolded. The work highlights the fact that when motional averaging is included, NMR data has only limited capacity to distinguish between a single fully folded peptide conformation and various mixtures of folded and unfolded conformations. Proteins 1999;36:542-555.