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Marsili S.,University of Florence | Marsili S.,Centro Interdipartimentale per lo Studio Delle Dinamiche Complesse CSDC | Signorini G.F.,University of Florence | Signorini G.F.,Centro Interdipartimentale per lo Studio Delle Dinamiche Complesse CSDC | And 5 more authors.
Journal of Computational Chemistry | Year: 2010

We present the new release of the ORAC engine (Procacci et al., Comput Chem 1997, 18, 1834), a FORTRAN suite to simulate complex biosystems at the atomistic level. The previous release of the ORAC code included multiple time steps integration, smooth particle mesh Ewald method, constant pressure and constant temperature simulations. The present release has been supplemented with the most advanced techniques for enhanced sampling in atomistic systems including replica exchange with solute tempering, metadynamics and steered molecular dynamics. All these computational technologies have been implemented for parallel architectures using the standard MPI communication protocol. ORAC is an open-source program distributed free of charge under the GNU general public license (GPL) at http://www.chim.unifi.it/orac. © 2009 Wiley Periodicals, Inc.

Nicolini P.,University of Florence | Procacci P.,University of Florence | Procacci P.,Centro Interdipartimentale per Lo Studio Delle Dinamiche Complesse CSDC | Chelli R.,University of Florence | Chelli R.,CNR Institute of Applied Physics Nello Carrara
Journal of Physical Chemistry B | Year: 2010

In the framework of single-molecule pulling experiments, the system is typically driven out of equilibrium by a time-dependent external potential V(t) acting on a collective coordinate such that the total Hamiltonian is the sum of V(t) and the Hamiltonian in the absence of external perturbation. Nonequilibrium work theorems such as Jarzynski equality and Crooks fluctuation theorem have been devised to recover free energy differences between states of this extended system. However, one is often more interested in the potential of mean force of the unperturbed Hamiltonian, i.e., in the effective potential dictating the equilibrium distribution of the collective coordinate in the absence of the external potential. In this respect, Hummer and Szabo proposed an algorithm to estimate the desired free energy differences when pulling experiments are performed in only one direction of the process (Proc. Natl. Acad. Sci. USA 2001, 98, 3658). In this paper, we present a potential of mean force estimator of the unperturbed system that exploits the work measured in both forward and backward directions of the process. The method is based on the reweighting technique of Hummer and Szabo and on the Bennett acceptance ratio. Using Brownian-dynamics simulations on a double-well free energy surface, we show that the estimator works satisfactorily in any pulling situation, from nearly equilibrium to strongly dissipative regimes. The method is also applied to the unfolding/refolding process of decaalanine, a system vastly used to illustrate and to test nonequilibrium methodologies. A thorough comparative analysis with another bidirectional potential of mean force estimator (Minh, D. D. L.; Adib, A. B. Phys. Rev. Lett. 2008, 100, 180602) is also presented. The proposed approach is well-suited to recover free energy profiles from single-molecule bidirectional-pulling experiments such as those performed by optical tweezers or atomic force microscopes. © 2010 American Chemical Society.

Bizzarri M.,University of Florence | Marsili S.,University of Florence | Procacci P.,University of Florence | Procacci P.,Centro Interdipartimentale per Lo Studio Delle Dinamiche Complesse CSDC
Journal of Physical Chemistry B | Year: 2011

The conformational landscape of three FK506-related drugs with disparate inhibition constants is determined in bulk solution using a replica exchange simulation method with solute torsional tempering. Energetic fitness of important drug conformations with respect to the FKBP12 protein is evaluated by molecular mechanics. Results show that the experimental affinity toward peptidyl-prolyl cis-trans isomerase protein (FKBP12) of the analyzed ligands appears to be positively correlated to the observed population of specific chair structures of the drug piperidinic ring in bulk solution. This observation is rationalized on the basis that such structures, stabilized by stereospecific intramolecular hydrophobic interactions, allows the formation of a pair of protein-ligand hydrogen bonds upon binding. © 2011 American Chemical Society.

Procacci P.,University of Florence | Procacci P.,Centro Interdipartimentale per Lo Studio Delle Dinamiche Complesse CSDC
Journal of Chemical Physics | Year: 2015

In this paper, we present an improved method for obtaining unbiased estimates of the free energy difference between two thermodynamic states using the work distribution measured in nonequilibrium driven experiments connecting these states. The method is based on the assumption that any observed work distribution is given by a mixture of Gaussian distributions, whose normal components are identical in either direction of the nonequilibrium process, with weights regulated by the Crooks theorem. Using the prototypical example for the driven unfolding/folding of deca-alanine, we show that the predicted behavior of the forward and reverse work distributions, assuming a combination of only two Gaussian components with Crooks derived weights, explains surprisingly well the striking asymmetry in the observed distributions at fast pulling speeds. The proposed methodology opens the way for a perfectly parallel implementation of Jarzynski-based free energy calculations in complex systems. © 2015 AIP Publishing LLC.

Procacci P.,University of Florence | Procacci P.,Centro Interdipartimentale per Lo Studio Delle Dinamiche Complesse CSDC
Annual Reports on the Progress of Chemistry - Section C | Year: 2011

This contribution is aimed at assessing the current knowledge of stacking interactions in proteins focusing on the thermodynamic origin of their strength. First, the energetic nature of π-π interactions is critically discussed by using recent accurate quantum chemical calculations. Then, the intimate relation between energetics and thermodynamics is analyzed via a survey on the last decade computer simulations and experimental data involving interactions of aromatic side chains in solution. The thermodynamics of stacking in protein is further assessed by reviewing studies based on a knowledge-based approach on updated databases of experimental protein structures. Finally the contribution selectively includes some recent authoritative progresses that highlights the paramount importance of stacking in the stabilization and destabilization of protein tertiary structures. © 2011 The Royal Society of Chemistry.

Procacci P.,University of Florence | Marsili S.,Centro Interdipartimentale per Lo Studio Delle Dinamiche Complesse CSDC
Chemical Physics | Year: 2010

We present non equilibrium molecular dynamics experiments of the unfolding and refolding of a single molecule alanine decapeptide in vacuo subject to a Nosé thermostat. Forward (unfolding) and reverse (refolding) work distribution are numerically calculated for various duration times of the non equilibrium experiments. Crooks theorem is accurately verified for all non equilibrium regimes and the time asymmetry of the process is measured using the recently proposed Jensen-Shannon divergence [E.H. Feng, G. Crooks, Phys. Rev. Lett. 101, 090602 (2008)]. Results on the alanine decapeptide are found similar to recent experimental data on m-RNA molecule in solution, thus evidencing the universal character of the Jensen-Shannon divergence. The patent non Markovianity of the process is rationalized by assuming that the observed forward and reverse distributions can be each described by a combination of two normal distributions satisfying the Crooks theorem, representative of two mutually exclusive linear events. Such bimodal approach reproduces with surprising accuracy the observed non Markovian work distributions. © 2010 Elsevier B.V. All rights reserved.

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