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Molecular dynamics simulation free energy

Pablo G Romano, Marina Giuseppina Guenza
Markov State Models (MSM) are used to model the kinetics of processes sampled by Molecular Dynamics (MD) simulations. MSM reduce the high dimensionality inherent to MD simulations as they partition the free energy landscape into discrete states, generating a kinetic model as a series of uncorrelated jumps between states. Here, we detail a new method, called GRadient Adaptive Decomposition, which optimizes coarse-grained MSM by refining borders with respect to the gradient along the free energy surface. The proposed method requires only a small number of initial microstates because it corrects for errors produced by limited sampling...
October 16, 2017: Journal of Chemical Information and Modeling
Thierry O Wambo, Liao Y Chen, Clyde Phelix, George Perry
Glucose transporters (GLUTs), expressed in all types of human cells, are responsible for the uptake of sugars as the primary energy source for the normal functions of good cells and for the abnormal growth of cancer cells. The E. coli xylose permease (XylE), a homologue of human GLUTs, has been investigated more thoroughly than other major facilitator proteins in the current literature. In this paper, we present a molecular dynamics (MD) study of an all-atom model system to elucidate the atomistic details and the free-energy landscape along the path of binding a xylopyranose (XYP) from the extracellular space to the inside of the transporter protein XylE...
October 11, 2017: Biochemical and Biophysical Research Communications
Inna Ermilova, Samuel Stenberg, Alexander P Lyubartsev
A series of 19 hydroxylated polybrominated diphenyl ethers (OH-PBDEs) have been studied using density functional theory (DFT) and molecular dynamics simulations with the purpose of investigating eventual correlations between their physicochemical properties and toxic action. Dissociation constants (pKa), solvation free energies and octanol-water partition coefficients (log P) have been computed. Additionally, metadynamics simulations of OH-PBDEs passing through a lipid bilayer have been carried out for four OH-PBDE species...
October 13, 2017: Physical Chemistry Chemical Physics: PCCP
Dennis D Fernandes, Jasbir Bamrah, Senthilkumar Kailasam, Gregory-Neal W Gomes, Yuchong Li, Hans-Joachim Wieden, Claudiu C Gradinaru
In recent years, new labelling strategies have been developed that involve the genetic insertion of small amino-acid sequences for specific attachment of small organic fluorophores. Here, we focus on the tetracysteine FCM motif (FLNCCPGCCMEP), which binds to fluorescein arsenical hairpin (FlAsH), and the ybbR motif (TVLDSLEFIASKLA) which binds fluorophores conjugated to Coenzyme A (CoA) via a phosphoryl transfer reaction. We designed a peptide containing both motifs for orthogonal labelling with FlAsH and Alexa647 (AF647)...
October 12, 2017: Scientific Reports
Danfeng Shi, Qifeng Bai, Shuangyan Zhou, Xuewei Liu, Huanxiang Liu, Xiaojun Yao
As co-chaperones of the 90-kDa heat shock protein(HSP90), FK506 binding protein 51 (FKBP51) and FK506 binding protein 52 (FKBP52) modulate the maturation of steroid hormone receptor through their specific FK1 domains (FKBP12-like domain 1). The inhibitors targeting FK1 domains are potential therapies for endocrine-related physiological disorders. However, the structural conservation of the FK1 domains between FKBP51 and FKBP52 make it difficult to obtain satisfactory selectivity in FK506-based drug design. Fortunately, a series of iFit ligands synthesized by Hausch et al exhibited excellent selectivity for FKBP51, providing new opportunity for design selective inhibitors...
October 12, 2017: Proteins
Xingqing Xiao, Yiming Wang, Joshua N Leonard, Carol K Hall
To enhance the sampling efficiency of our computational peptide-design algorithm in conformational space, the concerted rotation (CONROT) technique is extended to enable larger conformational perturbations of peptide chains. This allows us to make relatively-large peptide conformation changes during the process of designing peptide sequences to bind with high affinity to a specific target. Searches conducted using the new algorithm identified six potential λ N(2-22) peptide variants, called B1 to B6, which bind to boxB RNA with high affinity...
October 12, 2017: Journal of Chemical Theory and Computation
Qinghua Liao, Anna Pabis, Birgit Strodel, Shina Caroline Lynn Kamerlin
Modeling metalloproteins often requires classical molecular dynamics (MD) simulations in order to capture their relevant motions, which in turn necessitates reliable descriptions of the metal centers involved. One of the most successful approaches to date is provided by the "cationic dummy model", where the positive charge of the metal ion is transferred towards dummy particles that are bonded to the central metal ion in a pre-defined coordination geometry. While this approach allows for ligand exchange, and captures the correct electrostatics as demonstrated for different divalent metal ions, current dummy models neglect ion-induced dipole interactions...
October 12, 2017: Journal of Physical Chemistry Letters
Jonas Elm
The molecular interactions between sulfuric acid (sa) and methylamine (ma) are investigated using computational methods. The molecular structures and vibrational frequencies of (sa)a(ma)b clusters, with a, b à 4 were obtained with the ωB97X-D func- tional using a 6-31++G(d,p) basis set. The single point energies were corrected us- ing the domain-based local pair natural orbital coupled cluster method - DLPNO- CCSD(T) - with an aug-cc-pVTZ basis set. The calculated Gibbs free energies (∆G) of the clusters are used to calculate the evaporation rates of the (sa)a(ma)b cluster sys- tem and compare them to the corresponding ammonia clusters...
October 11, 2017: Journal of Physical Chemistry. A
Christian Hanke, Holger Gohlke
Riboswitches are genetic regulatory elements mainly found in bacteria, which regulate gene expression based on the availability of a ligand. Purine-sensing riboswitches, including the guanine-sensing riboswitch (Gsw), possess tertiary interactions connecting the L2 and L3 loops. These interactions are important for ligand binding to the aptamer. However, atomic-level structural knowledge about the unbound state and how the tertiary interactions influence the conformational heterogeneity of the aptamer is still scarce...
October 11, 2017: Journal of Chemical Information and Modeling
Nicolas Panel, Young Joo Sun, Ernesto J Fuentes, Thomas Simonson
PDZ domains generally bind short amino acid sequences at the C-terminus of target proteins, and short peptides can be used as inhibitors or model ligands. Here, we used experimental binding assays and molecular dynamics simulations to characterize 51 complexes involving the Tiam1 PDZ domain and to test the performance of a semi-empirical free energy function. The free energy function combined a Poisson-Boltzmann (PB) continuum electrostatic term, a van der Waals interaction energy, and a surface area term. Each term was empirically weighted, giving a Linear Interaction Energy or "PB/LIE" free energy...
2017: Frontiers in Molecular Biosciences
Ana Patricia Gámiz-Hernández, Alexander Jussupow, Mikael P Johansson, Ville R I Kaila
Complex I functions as a redox-driven proton pump in aerobic respiratory chains. By reducing quinone (Q), complex I employs the free energy released in the process to thermodynamically drive proton pumping across its membrane domain. The initial Q reduction step plays a central role in activating the proton pumping machinery. In order to probe the energetics, dynamics, and molecular mechanism for the proton-coupled electron transfer (PCET) process linked to the Q reduction, we employ here multi-scale quantum and classical molecular simulations...
October 10, 2017: Journal of the American Chemical Society
Dawei Deng, Changlong Hao, Soumyo Sen, Chuanlai Xu, Petr Kral, Nicholas A Kotov
The ability of semiconductor nanoparticles (NPs) to self-assemble has been known for about three decades. However, the limits of the geometrical and functional complexity for the self-assembled nanostructures made from fairly simple building blocks are still continuing to amaze researchers. We report here the self-assembly of ~2-4 nm FeSe2 nanoparticles (NPs) with platelet-like shapes into single-crystal nanosheets with lateral dimensions of ~600 -1000 nm and thickness of ~5.5 nm. As the nanosheets formed, they spontaneously rolled into scrolls...
October 10, 2017: Journal of the American Chemical Society
Thomas Tarenzi, Vania Calandrini, Raffaello Potestio, Alejandro Giorgetti, Paolo Carloni
The recently proposed Hamiltonian Adaptive Resolution Scheme (H-AdResS) allows to perform molecular simulations in an open boundary framework. It allows to change on the fly the resolution of specific subset of molecules (usually the solvent), which are free to diffuse between the atomistic region and the coarse-grained reservoir. So far, the method has been successfully applied to pure liquids. Coupling the H-AdResS methodology to hybrid models of proteins, such as the Molecular Mechanics/Coarse-Grained (MM/CG) scheme, is a promising approach for rigorous calculations of ligand binding free energies in low-resolution protein models...
October 9, 2017: Journal of Chemical Theory and Computation
Parimal Kar, Michael Feig
Hybrid all-atom/coarse-grained (AA/CG) simulations of proteins offer a computationally efficient compromise where atomistic details are only applied to biologically relevant regions while benefitting from the speedup of treating the remaining parts of a given system at the CG level. The recently developed CG model, PRIMO, allows a direct coupling with an atomistic force field with no additional modifications or coupling terms and the ability to carry out dynamic simulations without any restraints on secondary or tertiary structures...
October 9, 2017: Journal of Chemical Theory and Computation
Hedieh Torabifard, G Andrés Cisneros
E. Coli AlkB catalyzes the direct dealkylation of various alkylated bases in damaged DNA. The diffusion of molecular oxygen to the active site in AlkB is an essential step for the oxidative dealkylation activity. Despite detailed studies on the stepwise oxidation mechanism of AlkB, there is no conclusive picture of how O2 molecules reach the active site of the protein. Yu et al. (Nature, 439, 879) proposed the existence of an intra-molecular tunnel based on their initial crystal structures of AlkB. We have employed computational simulations to investigate possible migration pathways inside AlkB for O2 molecules...
September 1, 2017: Chemical Science
Timothy T Duignan, Marcel D Baer, Gregory K Schenter, Christopher J Mundy
Single ion solvation free energies are one of the most important properties of electrolyte solutions and yet there is ongoing debate about what these values are. Only the values for neutral ion pairs are known. Here, we use DFT interaction potentials with molecular dynamics simulation (DFT-MD) combined with a modified version of the quasi-chemical theory (QCT) to calculate these energies for the lithium and fluoride ions. A method to correct for the error in the DFT functional is developed and very good agreement with the experimental value for the lithium fluoride pair is obtained...
September 1, 2017: Chemical Science
Babban Jee, Sanjay Kumar, Renu Yadav, Yogesh Singh, Anuj Kumar, Naveen Sharma
Small heat shock protein16.3 (sHSP16.3) is a crucial protein for survival of Mycobacterium tuberculosis (MTB) in its host. Besides, this protein acts as a molecular chaperone during stress and is indispensable for MTB's growth, virulence and cell wall thickening. sHSP16.3 is also a promising candidate for vaccine, serodiagnosis and drug design as well. In the present study, we have targeted sHSP16.3 with two phytochemicals namely ursolic acid and carvacrol using in silico approach. Molecular docking analysis showed that both phytochemicals (ursolic acid and carvacrol) has docked with sHSP16...
October 6, 2017: Journal of Biomolecular Structure & Dynamics
Émilie Bordes, Anabela J L Costa, Joanna Szala-Bilnik, Jean-Michel Andanson, José M S S Esperança, Margarida F Costa Gomes, José N Canongia Lopes, Agílio A H Pádua
The aim of this work is to understand the details of the interactions of ionic liquids with carbon nanomaterials (graphene and nanotubes) using polyaromatic compounds as model solutes. We have combined the measurements of thermodynamic quantities of solvation with molecular dynamics simulations to provide a microscopic view. The solubility of five polycyclic aromatic hydrocarbons (naphthalene, anthracene, phenanthrene, pyrene and coronene) was determined in seven ionic liquids ([C4C1im][C(CN)3], [C4C1pyrr][Ntf2], [C10C1im][Ntf2], [C2C1im][C(CN)3], [C2C1im][Ntf2], [C3C1pyrr][N(CN)2] and [C4C1im][N(CN)2]) at 298 K...
October 6, 2017: Physical Chemistry Chemical Physics: PCCP
Chenyu Wei, Andrew Pohorille
We investigate permeation of three blocked dipeptides with different side chain polarity across a phospholipid membrane and their behavior at the water-membrane interface by way of molecular dynamics simulations. Hydrophilic serine-serine dipeptide is found to desorb from the interface to aqueous phase, whereas hydrophobic phenylalanine-leucine and amphiphilic serine-leucine tend to accumulate at the interface with a free energy minimum of -3 kcal/mol. All three dipeptides exhibit free energy barriers to permeation across the membrane located at the center of the bilayer...
October 16, 2017: Journal of Physical Chemistry. B
Kayla G Sprenger, Arushi Prakash, Gary P Drobny, Jim Pfaendtner
Biomimetic silica formation, a process that is largely driven by proteins, has garnered considerable interest in recent years due to its role in the development of new biotechnologies. However, much remains unknown of the molecular-scale mechanisms underlying the binding of proteins to biomineral surfaces such as silica, or even of the key residue-level interactions between such proteins and surfaces. In this study, we employ molecular dynamics (MD) simulations to study the binding of R5 - a 19-residue segment of a native silaffin peptide used for in vitro silica formation - to a silica surface...
October 5, 2017: Langmuir: the ACS Journal of Surfaces and Colloids
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