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Molecular dynamics simulation free energy

Song-Ho Chong, Sihyun Ham
Interfacial waters are considered to play a crucial role in protein-protein interactions, but in what sense and why are they important? Here, using molecular dynamics simulations and statistical thermodynamic analyses, we demonstrate distinctive dynamic characteristics of the interfacial water and investigate their implications for the binding thermodynamics. We identify the presence of extraordinarily slow (~1,000 times slower than in bulk water) hydrogen-bond rearrangements in interfacial water. We rationalize the slow rearrangements by introducing the "trapping" free energies, characterizing how strongly individual hydration waters are captured by the biomolecular surface, whose magnitude is then traced back to the number of water-protein hydrogen bonds and the strong electrostatic field produced at the binding interface...
August 18, 2017: Scientific Reports
Qianqian Wang, Ying Li, Jiahui Xu, Yuwei Wang, Elaine Lai-Han Leung, Liang Liu, Xiaojun Yao
RVX-208 is a recently reported inhibitor of bromo and extraterminal (BET) family proteins (including BRD2-4 and BRDT) with selectivity for the second bromodomain (BD2), currently in phase III clinical trials. Despite of its promising antitumor activity, due to the conserved folds of the first and second bromodomains (BD1 and BD2), the detailed selectivity mechanism of RVX-208 towards BD2 over BD1 is still unknown. To elucidate selective inhibition mechanism of RVX-208 to BD2, microsecond molecular dynamics simulations were performed in this study for BRD2-BD1, BRD2-BD2 and BRD4-BD1 with and without RVX-208, respectively...
August 18, 2017: Scientific Reports
Adam W Duster, Hai Lin
Recently, a collective variable "proton indicator" was purposed for tracking an excess proton solvated in bulk water in molecular dynamics simulations. In this work, we demonstrate the feasibility of utilizing the position of this proton indicator as a reaction coordinate to model an excess proton migrating through a hydrophobic carbon nanotube in combined quantum-mechanics/molecular-mechanics simulations. Our results indicate that applying a harmonic restraint to the proton indicator in the bulk solvent near the nanotube pore entrance leads to the recruitment of water molecules into the pore...
August 18, 2017: Journal of Physical Chemistry. B
Ivan Kruglov, Oleg Sergeev, Alexey Yanilkin, Artem R Oganov
We used the machine learning technique of Li et al. (PRL 114, 2015) for molecular dynamics simulations. Atomic configurations were described by feature matrix based on internal vectors, and linear regression was used as a learning technique. We implemented this approach in the LAMMPS code. The method was applied to crystalline and liquid aluminum and uranium at different temperatures and densities, and showed the highest accuracy among different published potentials. Phonon density of states, entropy and melting temperature of aluminum were calculated using this machine learning potential...
August 17, 2017: Scientific Reports
Jie Sun, Hua Sheng Wang
In this work, we propose the concept to use the hydrophilic or neutral surface for condensation heat transfer and to use the superhydrophobic surface for enhancement by self-shedding and sweeping of condensate. Molecular dynamics simulation results show that no matter the vapor condenses on the solid surface in dropwise or filmwise mode, the grown-up condensate self-sheds and falls off the superhydrophobic surface, sweeping the growing condensate on the condensing surface downstream. We characterize the dynamics of condensate that the continuous self-shedding and sweeping effectively remove the droplets from the solid surface in dropwise mode or thin the condensate film on the solid surface in filmwise mode, which significantly enhances the condensation heat transfer...
August 17, 2017: Scientific Reports
J Lesitha Jeeva Kumari, R Jesu Jaya Sudan, C Sudandiradoss
Subunit reassociation in mucin 1, a breast cancer tumor marker, is reported as one of the critical factors for its cytoplasmic activation. Inhibition of its heterodimeric association would therefore result in loss of its function and alter disease progression. The present study aimed at evaluating peptide inhibitor designing strategies that may serve as antagonist against this receptor-ligand alliance. Several peptides and their derivatives were designed based on native residues, subunit interface, hydrogen bonding and secondary structure...
2017: PloS One
Son Tung Ngo, Minh Tung Nguyen, Nguyen Thanh Nguyen, Van V Vu
Familial Alzheimer's disease (FAD) is passed down in family, which account for 2-3% of about 40 million AD cases worldwide. The Flemish (A21G) mutant of amyloid β (Aβ) exhibits unique properties among all hereditary mutants of FAD, including lowest aggregation rate. Recent studies showed that Aβ oligomers play key role in Alzheimer's disease (AD) pathogenesis. They could insert themselves in brain cell membrane, disrupting the membrane integrity and ion homeostasis. However, experimental studies of transmembrane Aβ oligomers have been limited due to their intrinsic heterogeneity...
August 17, 2017: Journal of Physical Chemistry. B
Christian Solís-Calero, Hernandes F Carvalho
Kallikrein 14 (KLK14) is a serine protease linked to several pathologies including prostate cancer and positively correlates with Gleason score. Though KLK14 functioning in cancer is poorly understood, it has been implicated in HGF/Met signaling, given that KLK14 proteolytically inhibits HGF activator-inhibitor 1 (HAI-1), which strongly inhibits pro-HGF activators, thereby contributing to tumor progression. In this work, KLK14 binding to either hepatocyte growth factor activator inhibitor type-1 (HAI-1) or type-2 (HAI-2) was essayed using homology modeling, molecular dynamic simulations and free-energy calculations through MM/PBSA and MM/GBSA...
August 17, 2017: Cell Biology International
Oleg N Starovoytov, Pengzhi Zhang, Piotr Cieplak, Margaret S Cheung
The light-harvesting molecular triad consisting of carotenoid polyene (C), diaryl-porphyrin (P) and pyrrole-fullerene (C60) is a donor-acceptor molecule capable of absorbing incident light in the visible range. Its ability to convert solar energy to electrical excitation and charge separation energy suggests a great potential in real-world applications. The ensemble of its conformations under ambient conditions varies widely according to its electronic state. In previous work, we applied a non-polarizable model to study the conformational distribution of the molecular triad in the ground and charge separated states...
August 17, 2017: Physical Chemistry Chemical Physics: PCCP
Ezequiel L Murina, Roberto Fernández-Prini, Claudio Pastorino
We studied the behavior of long chain alkanes (LCAs) as they were transferred from gas to bulk water, through the liquid-vapor interface. These systems were studied using umbrella sampling molecular dynamics simulation and we have calculated properties like free energy profiles, molecular orientation, and radius of gyration of the LCA molecules. The results show changes in conformation of the solutes along the path. LCAs adopt pronounced molecular orientations and the larger ones extend appreciably when partially immersed in the interface...
August 14, 2017: Journal of Chemical Physics
Jianyi Wang, Qing Chen, Mian Wang, Cheng Zhong
To obtain new insights into the resistance caused by T315I and the differential selectivities of dasatinib and axitinib against BCR-ABL1(WT) and BCR-ABL1(T315), molecular dynamics simulations and free energy calculations were performed. A rule is summarized that the opening/closure of the P-loop and hinge of BCR-ABL1 could reflect the low/high bioactivities of dasatinib and axitinib. This may be because strong interactions of the ligands with key residues induce the P-loop and hinge of BCR-ABL1 to close, being favorable for the retention of the ligand in the binding site...
August 15, 2017: Physical Chemistry Chemical Physics: PCCP
Daniel Ciupka, Holger Gohlke
The pyruvate phosphate dikinase (PPDK) reaction mechanism is characterized by a distinct spatial separation of reaction centers and large conformational changes involving an opening-closing motion of the nucleotide-binding domain (NBD) and a swiveling motion of the central domain (CD). However, why PPDK is active only in a dimeric form and to what extent an alternate binding change mechanism could underlie this fact has remained elusive. We performed unbiased molecular dynamics simulations, configurational free energy computations, and rigidity analysis to address this question...
August 14, 2017: Scientific Reports
Jing Zhou, Micholas Dean Smith, Sarah J Cooper, Xiaolin Cheng, Jeremy C Smith, Jerry M Parks
Cellular uptake and export are important steps in the biotransformation of mercury (Hg) by microorganisms. However, the mechanisms of transport across biological membranes remain unclear. Membrane-bound transporters are known to be relevant, but passive permeation may also be involved. Inorganic Hg(II) and methylmercury ([CH3Hg]+) are commonly complexed with thiolate ligands. Here, we have performed extensive molecular dynamics simulations of the passive permeation of Hg(II) and [CH3Hg]+ complexes with thiolate ligands through a model bacterial cytoplasmic membrane...
August 14, 2017: Environmental Science & Technology
Emmi Pohjolainen, Sami Malola, Gerrit Groenhof, Hannu Häkkinen
Bio-compatible gold nanoclusters can be utilized as contrast agents in virus imaging. The labeling of viruses can be achieved non-covalently but site-specifically by linking the cluster to the hydrophobic pocket of a virus via a lipid-like pocket factor. We have estimated the binding affinities of three different pocket factors of echovirus 1 (EV1) in molecular dynamics simulations combined with non-equilibrium free energy calculations. We have also studied the effects on binding affinities with a pocket factor linked to the Au102pMBA44 nanocluster in different protonation states...
August 14, 2017: Bioconjugate Chemistry
Xiaoxia He, Yan Shen, Francisco R Hung, Erik E Santiso
Classical molecular dynamics simulations were used to study the nucleation of the crystal phase of the ionic liquid [dmim(+)][Cl(-)] from its supercooled liquid phase, both in the bulk and in contact with a graphitic surface of D = 3 nm. By combining the string method in collective variables [Maragliano et al., J. Chem. Phys. 125, 024106 (2006)], with Markovian milestoning with Voronoi tessellations [Maragliano et al., J. Chem. Theory Comput. 5, 2589-2594 (2009)] and order parameters for molecular crystals [Santiso and Trout, J...
December 7, 2016: Journal of Chemical Physics
Matteo Salvalaglio, Pratyush Tiwary, Giovanni Maria Maggioni, Marco Mazzotti, Michele Parrinello
Condensation of a liquid droplet from a supersaturated vapour phase is initiated by a prototypical nucleation event. As such it is challenging to compute its rate from atomistic molecular dynamics simulations. In fact at realistic supersaturation conditions condensation occurs on time scales that far exceed what can be reached with conventional molecular dynamics methods. Another known problem in this context is the distortion of the free energy profile associated to nucleation due to the small, finite size of typical simulation boxes...
December 7, 2016: Journal of Chemical Physics
Chan-Fei Su, Holger Merlitz, Hauke Rabbel, Jens-Uwe Sommer
Using coarse-grained molecular dynamics simulations, we study the passive translocation of nanoparticles with a size of about 1 nm and with tunable degrees of hydrophobicity through lipid bilayer membranes. We observe a window of translocation with a sharp maximum for nanoparticles having a hydrophobicity in between hydrophilic and hydrophobic. Passive translocation can be identified as diffusive motion of individual particles in a free energy landscape. By combining direct sampling with umbrella-sampling techniques we calculate the free energy landscape for nanoparticles covering a wide range of hydrophobicities...
August 16, 2017: Journal of Physical Chemistry Letters
Shuangyan Zhou, Xuewei Liu, Xiaoli An, Xiaojun Yao, Huanxiang Liu
Structural transitions in the prion protein from the cellular form, PrP(C), into the pathological isoform, PrP(Sc), are regarded as the main cause of the transmissible spongiform encephalopathies, also known as prion diseases. Hence, discovering and designing effective antiprion drugs that can inhibit PrP(C) to PrP(Sc) conversion is regarded as a promising way to cure prion disease. Among several strategies to inhibit PrP(C) to PrP(Sc) conversion, stabilizing the native PrP(C) via specific binding is believed to be one of the valuable approaches and many antiprion compounds have been reported based on this strategy...
August 22, 2017: ACS Chemical Neuroscience
Parthiban Marimuthu, Pavithra K Balasubramanian, Kalaimathy Singaravelu
The Bcl-2 family proteins are the central regulators of apoptosis. Due to its predominant role in cancer progression, the Bcl-2 family proteins act as attractive therapeutic targets. Recently,molecular series of BenzothiazoleHydrazone(BH) inhibitorsthat exhibits drug-likenesscharacteristics,whichselectivelytargets Bcl-xLhave been reported.In the present study,dockingwas used toexplore the plausible binding mode of the highly active BH inhibitorwith Bcl-xL;and Molecular Dynamics(MD) simulation wasapplied toinvestigate the stability of predicted conformationover time...
August 10, 2017: Journal of Biomolecular Structure & Dynamics
Jhonny Azuaje, Willem Jespers, Vicente Yaziji, Ana Mallo, María Majellaro, Olga Caamaño, María I Loza, María I Cadavid, José M Brea, Johan Åqvist, Eddy Sotelo, Hugo Gutiérrez de Terán
We report the first family of 2-acetamidopyridines as potent and selective A3 adenosine receptor (AR) antagonists. The computer-assisted design was focused on the bioisosteric replacement of the N1 atom by a CH group in a previous series of diarylpyrimidines. Some of the generated 2-acetamidopyridines elicit antagonistic effect with excellent affinity (Ki < 10 nM) and outstanding selectivity profiles, providing an alternative and simpler chemical scaffold to the parent series of diarylpyrimidines. In addition, by molecular dynamics and free energy perturbation simulations we elucidate the effect of the second nitrogen of the parent diarylpyrimidines, which is revealed as a stabilizer of a water network in the binding site...
August 9, 2017: Journal of Medicinal Chemistry
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