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The use of the Ehrenfest method to simulate the relaxation of molecules in solution is explored. Using the cyanide ion dissolved in water as a test model, the independent trajectory (IT) and the bundle of trajectories (BT) approximations are shown to provide very different results for the time evolution of the vibrational populations of the solute. None of these approximations reproduce the Boltzmann equilibrium vibrational populations accurately. A modification of the Ehrenfest method based on the use of quantum correction factors is thus proposed to solve this problem. The simulations carried out using the modified Ehrenfest method provide IT and BT relaxation times which are closer to each other and which agree quite well with previous hybrid perturbative results.

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Edited by Norma AllewellThe Staphylococcus aureus cell surface contains cell wall-anchored proteins such as fibronectin-binding protein A (FnBPA) that bind to host ligands (e.g. fibronectin; Fn) present in the extracellular matrix of tissue or coatings on cardiac implants. Recent clinical studies have found a correlation between cardiovascular infections caused by S. aureus and nonsynonymous SNPs inFnBPA. Atomic force microscopy (AFM), surface plasmon resonance (SPR), and molecular simulations were used to investigate interactions between Fn and each of eight 20-mer peptide variants containing amino acids Ala, Asn, Gln, His, Ile, and Lys at positions equivalent to 782 and/or 786 in Fn-binding repeat-9 of FnBPA. Experimentally measured bond lifetimes (1/k off ) and dissociation constants (K d ‫؍‬ k off /k on ), determined by mechanically dissociating the Fn⅐peptide complex at loading rates relevant to the cardiovascular system, varied from the lowest-affinity H782A/K786A peptide (0.011 s, 747 M) to the highest-affinity H782Q/K786N peptide (0.192 s, 15.7 M). These atomic force microscopy results tracked remarkably well to metadynamics simulations in which peptide detachment was defined solely by the free-energy landscape. Simulations and SPR experiments suggested that an Fn conformational change may enhance the stability of the binding complex for peptides with K786I or H782Q/K786I (K d app ‫؍‬ 0.2-0.5 M, as determined by SPR) compared with the lowest-affinity double-alanine peptide (K d app ‫؍‬ 3.8 M). Together, these findings demon-. 4 The abbreviations used are: Fn, fibronectin; AFM, atomic force microscopy; COM, center of mass; CV, collective variable; FnBPA, fibronectin-binding protein A; FnBR-9, fibronectin-binding repeat 9 in FnBPA; MD, molecular dynamics; MSCRAMM, molecular surface component recognizing adhesive matrix molecule; NTD, N-terminal domain; SPR, surface plasmon resonance; nN and pN, nanonewton and piconewton, respectively. cros ARTICLE

The plasma membrane Ca ATPases (PMCA pumps) have a long, cytosolic C-terminal regulatory region where a calmodulin-binding domain (CaM-BD) is located. Under basal conditions (low Ca), the C-terminal tail of the pump interacts with autoinhibitory sites proximal to the active center of the enzyme. In activating conditions (i.e., high Ca), Ca-bound CaM displaces the C-terminal tail from the autoinhibitory sites, restoring activity. We have recently identified a G1107D replacement within the CaM-BD of isoform 3 of the PMCA pump in a family affected by X-linked congenital cerebellar ataxia. Here, we investigate the effects of the G1107D replacement on the interplay of the mutated CaM-BD with both CaM and the pump core, by combining computational, biochemical and functional approaches. We provide evidence that the affinity of the isolated mutated CaM-BD for CaM is significantly reduced with respect to the wild type (wt) counterpart, and that the ability of CaM to activate the pump in vitro is thus decreased. Multiscale simulations support the conclusions on the detrimental effect of the mutation, indicating reduced stability of the CaM binding. We further show that the G1107D replacement impairs the autoinhibition mechanism of the PMCA3 pump as well, as the introduction of a negative charge perturbs the contacts between the CaM-BD and the pump core. Thus, the mutation affects both the ability of the pump to optimally transport Ca in the activated state, and the autoinhibition mechanism in its resting state.