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When developing coarse‐grained models of complex processes out of equilibrium, one encounters the non‐stationary generalized Langevin equation. The most important feature of this equation is the presence of a non‐stationary memory kernel. Here, a method is presented to infer this memory kernel from MD simulation data in non‐equilibrium processes. The method provides an improvement of a previously published numerical scheme, the applicability of which is limited by a truncation problem. As an illustration, the method is applied to ion dissociation of NaCl in water, for which non‐trivial dampened oscillations are observed in the memory kernel. [ABSTRACT FROM AUTHOR]

ABSTRACT A local perturbation of a protein may lead to functional changes at some distal site, a phenomenon denoted as allostery. Here, we study the allosteric control of a protease using molecular dynamics simulations. The system considered is the bacterial protein DegS which includes a protease domain activated on ligand binding to an adjacent PDZ domain. Starting from crystallographic structures of DegS homo-trimers, we perform simulations of the ligand-free and -bound state of DegS at equilibrium. Considering a single protomer only, the trimeric state was mimicked by applying restraints on the residues in contact with other protomers in the DegS trimer. In addition, the bound state was also simulated without any restraints to mimic the monomer. Our results suggest that not only ligand release but also disassembly of a DegS trimer inhibits proteolytic activity. Considering various observables for structural changes, we infer allosteric pathways from the interface with other protomers to the active site. Moreover, we study how ligand release leads to (i) catalytically relevant changes involving residues 199-201 and (ii) a transition from a stretched to a bent conformation for residues 217-219 (which prohibits proper substrate binding). Finally, based on ligand-induced Cα shifts we identify residues in contact with other protomers in the DegS trimer that likely transduce the perturbation from ligand release from a given protomer to adjacent protomers. These residues likely play a key role in the experimentally known effect of ligand release from a protomer on the proteolytic activity of the other protomers. Proteins 2016; 84:1690-1705. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The cover image, by Volker Knecht et al., is based on the Article Mechanisms for allosteric activation of protease DegS by ligand binding and oligomerization as revealed from molecular dynamics simulations, DOI: 10.1002/prot.25154. [ABSTRACT FROM AUTHOR]

Employing extensive quantum-chemical calculations at the DFT/B3LYP and MP2 level, quartic force fields of isolated N-methylacetamide are constructed. Taking into account 24 vibrational degrees of freedom, the model is employed to perform numerically exact vibrational configuration interaction calculations of the vibrational energy relaxation of the amide I mode. It is found that the energy transfer pathways may sensitively depend on details of the theoretical description. Moreover, the exact reference calculations were used to study the applicability and accuracy of (i) the quasiclassical trajectory method, (ii) time-dependent second-order perturbation theory, and (iii) the instantaneous normal mode description of frequency fluctuations. Based on the results, several strategies to describe vibrational energy relaxation in biomolecular systems are discussed. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2009 [ABSTRACT FROM AUTHOR]

The free energy landscape and the folding mechanism of the C-terminal β-hairpin of protein G is studied by extensive replica exchange molecular dynamics simulations (40 replicas and 340 ns total simulation time), using the GROMOS96 force field and the SPC explicit water solvent. The study reveals that the system preferentially adopts a β-hairpin structure at biologically important temperatures, and that the helix content is low at all temperatures studied. Representing the free energy landscape as a function of several types of reaction coordinates, four local minima corresponding to the folded, partially folded, molten globule, and unfolded states are identified. The findings suggest that the folding of the β-hairpin occurs as the sequence: collapse of hydrophobic core → formation of H-bond → formation of the turn. Identifying the folded and molten globule states as the main conformations, the free energy landscape of the β-hairpin is consistent with a two-state behavior with a broad transition state. The temperature dependence of the folding-unfolding transition is investigated in some detail. The enthalpy and entropy jumps at the folding transition temperature are found to be about three times lower than the experimental estimates, indicating that the folding-unfolding transition in silico is less cooperative than its in vitro counterpart. Proteins 2005. © 2005 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

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A 100 ns molecular dynamics simulation of penta-alanine in explicit water is performed to study the reversible folding and unfolding of the peptide. Employing a standard principal component analysis (PCA) using Cartesian coordinates, the resulting free-energy landscape is found to have a single minimum, thus suggesting a simple, relatively smooth free-energy landscape. Introducing a novel PCA based on a transformation of the peptide dihedral angles, it is found, however, that there are numerous free energy minima of comparable energy (≲ 1 kcal/mol), which correspond to well-defined structures with characteristic hydrogen-bonding patterns. That is, the true free-energy landscape is actually quite rugged and its smooth appearance in the Cartesian PCA represents an artifact of the mixing of internal and overall motion. Well-separated minima corresponding to specific conformational structures are also found in the unfolded part of the free energy landscape, revealing that the unfolded state of penta-alanine is structured rather than random. Performing a connectivity analysis, it is shown that neighboring states are connected by low barriers of similar height and that each state typically makes transitions to three or four neighbor states. Several principal pathways for helix nucleation are identified and discussed in some detail. Proteins 2005. © 2004 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Based on the mapping formulation of nonadiabatic dynamics (Phys. Rev. Lett. 1997, 78, 578), explicit classical expressions for the total level density N(E) of a vibronically coupled molecular system as well as quantum corrections to it are derived. The analytical results for N(E) reveal the relative importance of the various molecular parameters of a curve-crossing system, such as the electronic bias, the reorganization energy, and the topology of the potential-energy surfaces. To study the accuracy of the approximate description, numerical studies employing various spin-boson models as well as a two-state, three-mode model of the ultrafast S 2 S 1 electronic relaxation in pyrazine are presented. Comparing exact quantum and approximate classical data, the connection between the level density of a vibronically coupled molecular system and its nonadiabatic relaxation behavior is discussed in some detail. [ABSTRACT FROM AUTHOR]