Enantiomerization of Axially Chiral Biphenyls: Polarizable MD Simulations in Water and Butylmethylether

In this study, we investigate the influence of chiral and achiral cations on the enantiomerization of biphenylic anions in n-butylmethylether and water. In addition to the impact of the cations and solvent molecules on the free energy profile of rotation, we also explore if chirality transfer between a chiral cation and the biphenylic anion is possible, i.e., if pairing with a chiral cation can energetically favour one conformer of the anion via diastereomeric complex formation. The quantum-mechanical calculations are accompanied by polarizable MD simulations using umbrella sampling to study the impact of solvents of different polarity in more detail. We also discuss how accurate polarizable force fields for biphenylic anions can be constructed from quantum-mechanical reference data.

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Phospholipid-Cellulose Interactions: Insight from Atomistic Computer Simulations for Understanding the Impact of Cellulose-Based Materials on Plasma Membranes

10.1101/425686 ◽

2018 ◽

Author(s):

Andrey A. Gurtovenko ◽

Evgenii I. Mukhamadiarov ◽

Andrei Yu. Kostritskii ◽

Mikko Karttunen

Keyword(s):

Hydrogen Bonds ◽

Plasma Membranes ◽

Md Simulations ◽

Umbrella Sampling ◽

Atomic Scale ◽

Pronounced Difference ◽

Dominant Component ◽

Head Groups ◽

The Impact ◽

Cellulose Surface

AbstractCellulose is an important biocompatible and nontoxic polymer widely used in numerous biomedical applications. The impact of cellulose-based materials on cells and, more specifically, on plasma membranes that surround cells, however, remains poorly understood. To this end, here we performed atomic-scale molecular dynamics (MD) simulations of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) bilayers interacting with the surface of a cellulose crystal. Both biased umbrella sampling and unbiased simulations clearly show the existence of strong attractive interactions between phospholipids and cellulose: the free energy of the cellulose-bilayer binding was found to be −1.89 and −1.96 kJ/mol per cellulose dimer for PC and PE bilayers, respectively. Although the values are similar, there is a pronounced difference between PC and PE bilayers. The driving force in both cases is the formation of hydrogen bonds. There are two distinct types of hydrogen bonds: 1) between the lipid head groups and the hydroxyl (hydroxymethyl) groups of cellulose, and 2) lipid-water and cellulose-water bonds. The former is the dominant component for PE systems whereas the latter dominates in PC systems. This suggests that achieving controlled binding via new cellulose modifications must pay close attention to the lipid head groups involved. The observed attractive phospholipid-cellulose interactions have a significant impact on bilayer properties: a cellulose crystal induces noticeable structural perturbations on the bilayer leaflet next to the crystal. Given that such perturbations can be undesirable when it comes to the interactions of cellulose-based materials with cell membranes, our computational studies suggest that the impact of cellulose could be reduced through chemical modification of the cellulose surface which prevents cellulose-phospholipid hydrogen bonding.

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Recent Advances of In-Silico Modeling of Potent Antagonists for the Adenosine Receptors

Current Pharmaceutical Design ◽

10.2174/1381612825666190304123545 ◽

2019 ◽

Vol 25 (7) ◽

pp. 750-773 ◽

Cited By ~ 11

Author(s):

Pabitra Narayan Samanta ◽

Supratik Kar ◽

Jerzy Leszczynski

Keyword(s):

Drug Targets ◽

Biological Activities ◽

Scoring Function ◽

Md Simulations ◽

Energy Calculation ◽

Binding Modes ◽

Macromolecular Systems ◽

In Silico Modeling ◽

Mathematical Algorithms ◽

The Impact

The rapid advancement of computer architectures and development of mathematical algorithms offer a unique opportunity to leverage the simulation of macromolecular systems at physiologically relevant timescales. Herein, we discuss the impact of diverse structure-based and ligand-based molecular modeling techniques in designing potent and selective antagonists against each adenosine receptor (AR) subtype that constitutes multitude of drug targets. The efficiency and robustness of high-throughput empirical scoring function-based approaches for hit discovery and lead optimization in the AR family are assessed with the help of illustrative examples that have led to nanomolar to sub-micromolar inhibition activities. Recent progress in computer-aided drug discovery through homology modeling, quantitative structure-activity relation, pharmacophore models, and molecular docking coupled with more accurate free energy calculation methods are reported and critically analyzed within the framework of structure-based virtual screening of AR antagonists. Later, the potency and applicability of integrated molecular dynamics (MD) methods are addressed in the context of diligent inspection of intricated AR-antagonist binding processes. MD simulations are exposed to be competent for studying the role of the membrane as well as the receptor flexibility toward the precise evaluation of the biological activities of antagonistbound AR complexes such as ligand binding modes, inhibition affinity, and associated thermodynamic and kinetic parameters.

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Spontaneous and frequent conformational dynamics induced by A…A mismatch in d(CAA)·d(TAG) duplex

Scientific Reports ◽

10.1038/s41598-021-82669-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yogeeshwar Ajjugal ◽

Kripi Tomar ◽

D. Krishna Rao ◽

Thenmalarchelvi Rathinavelan

Keyword(s):

Mismatch Repair ◽

Conformational Dynamics ◽

Md Simulations ◽

Umbrella Sampling ◽

Base Flipping ◽

Base Pairs ◽

2D Noesy ◽

Junction Formation ◽

Nmr Techniques ◽

Transient Events

AbstractBase pair mismatches in DNA can erroneously be incorporated during replication, recombination, etc. Here, the influence of A…A mismatch in the context of 5′CAA·5′TAG sequence is explored using molecular dynamics (MD) simulation, umbrella sampling MD, circular dichroism (CD), microscale thermophoresis (MST) and NMR techniques. MD simulations reveal that the A…A mismatch experiences several transient events such as base flipping, base extrusion, etc. facilitating B–Z junction formation. A…A mismatch may assume such conformational transitions to circumvent the effect of nonisostericity with the flanking canonical base pairs so as to get accommodated in the DNA. CD and 1D proton NMR experiments further reveal that the extent of B–Z junction increases when the number of A…A mismatch in d(CAA)·d(T(A/T)G) increases (1–5). CD titration studies of d(CAA)·d(TAG)n=5 with the hZαADAR1 show the passive binding between the two, wherein, the binding of protein commences with B–Z junction recognition. Umbrella sampling simulation indicates that the mismatch samples anti…+ syn/+ syn…anti, anti…anti & + syn…+ syn glycosyl conformations. The concomitant spontaneous transitions are: a variety of hydrogen bonding patterns, stacking and minor or major groove extrahelical movements (with and without the engagement of hydrogen bonds) involving the mismatch adenines. These transitions frequently happen in anti…anti conformational region compared with the other three regions as revealed from the lifetime of these states. Further, 2D-NOESY experiments indicate that the number of cross-peaks diminishes with the increasing number of A…A mismatches implicating its dynamic nature. The spontaneous extrahelical movement seen in A…A mismatch may be a key pre-trapping event in the mismatch repair due to the accessibility of the base(s) to the sophisticated mismatch repair machinery.

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Structural insights into the repair mechanism of AGT for methyl-induced DNA damage

Biological Chemistry ◽

10.1515/hsz-2021-0198 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Rajendra P. Koirala ◽

Rudramani Pokhrel ◽

Prabin Baral ◽

Purushottam B. Tiwari ◽

Prem P. Chapagain ◽

...

Keyword(s):

Covalent Bond ◽

Cancer Therapeutics ◽

Md Simulations ◽

Structural Features ◽

Umbrella Sampling ◽

Repair Mechanism ◽

Structural Investigations ◽

Methylated Dna ◽

Dna Base ◽

Dna Alkyltransferase

Abstract Methylation induced DNA base-pairing damage is one of the major causes of cancer. O6-alkylguanine-DNA alkyltransferase (AGT) is considered a demethylation agent of the methylated DNA. Structural investigations with thermodynamic properties of the AGT-DNA complex are still lacking. In this report, we modeled two catalytic states of AGT-DNA interactions and an AGT-DNA covalent complex and explored structural features using molecular dynamics (MD) simulations. We utilized the umbrella sampling method to investigate the changes in the free energy of the interactions in two different AGT-DNA catalytic states, one with methylated GUA in DNA and the other with methylated CYS145 in AGT. These non-covalent complexes represent the pre- and post-repair complexes. Therefore, our study encompasses the process of recognition, complex formation, and separation of the AGT and the damaged (methylated) DNA base. We believe that the use of parameters for the amino acid and nucleotide modifications and for the protein-DNA covalent bond will allow investigations of the DNA repair mechanism as well as the exploration of cancer therapeutics targeting the AGT-DNA complexes at various functional states as well as explorations via stabilization of the complex.

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High-resolution mining of the SARS-CoV-2 main protease conformational space: supercomputer-driven unsupervised adaptive sampling

Chemical Science ◽

10.1039/d1sc00145k ◽

2021 ◽

Author(s):

Théo Jaffrelot Inizan ◽

Frédéric Célerse ◽

Olivier Adjoua ◽

Dina El Ahdab ◽

Luc-Henri Jolly ◽

...

Keyword(s):

Molecular Dynamics ◽

High Resolution ◽

Adaptive Sampling ◽

Force Fields ◽

Sampling Strategy ◽

Md Simulations ◽

Conformational Space ◽

Many Body ◽

Polarizable Force Fields ◽

Main Protease

We provide an unsupervised adaptive sampling strategy capable of producing μs-timescale molecular dynamics (MD) simulations of large biosystems using many-body polarizable force fields (PFFs).

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Structural genomics approach to investigate deleterious impact of nsSNPs in conserved telomere maintenance component 1

Scientific Reports ◽

10.1038/s41598-021-89450-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Arunabh Choudhury ◽

Taj Mohammad ◽

Nikhil Samarth ◽

Afzal Hussain ◽

Md. Tabish Rehman ◽

...

Keyword(s):

Noncovalent Interactions ◽

Md Simulations ◽

Telomere Maintenance ◽

Nucleotide Polymorphisms ◽

Telomeric Dna ◽

Congenital Diseases ◽

Ob Fold ◽

Significant Conformational Change ◽

The Stability ◽

The Impact

AbstractConserved telomere maintenance component 1 (CTC1) is an important component of the CST (CTC1-STN1-TEN1) complex, involved in maintaining the stability of telomeric DNA. Several non-synonymous single-nucleotide polymorphisms (nsSNPs) in CTC1 have been reported to cause Coats plus syndrome and Dyskeratosis congenital diseases. Here, we have performed sequence and structure analyses of nsSNPs of CTC1 using state-of-the-art computational methods. The structure-based study focuses on the C-terminal OB-fold region of CTC1. There are 11 pathogenic mutations identified, and detailed structural analyses were performed. These mutations cause a significant disruption of noncovalent interactions, which may be a possible reason for CTC1 instability and consequent diseases. To see the impact of such mutations on the protein conformation, all-atom molecular dynamics (MD) simulations of CTC1-wild-type (WT) and two of the selected mutations, R806C and R806L for 200 ns, were carried out. A significant conformational change in the structure of the R806C mutant was observed. This study provides a valuable direction to understand the molecular basis of CTC1 dysfunction in disease progression, including Coats plus syndrome.

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Structural Properties of G,T-Parallel Duplexes

Journal of Nucleic Acids ◽

10.4061/2010/763658 ◽

2010 ◽

Vol 2010 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Anna Aviñó ◽

Elena Cubero ◽

Raimundo Gargallo ◽

Carlos González ◽

Modesto Orozco ◽

...

Keyword(s):

Molecular Dynamics ◽

Structural Properties ◽

Theoretical Calculations ◽

Md Simulations ◽

Theoretical Studies ◽

Duplex Structure ◽

Strong Stabilization ◽

The Stability ◽

The Impact

The structure of G,T-parallel-stranded duplexes of DNA carrying similar amounts of adenine and guanine residues is studied by means of molecular dynamics (MD) simulations and UV- and CD spectroscopies. In addition the impact of the substitution of adenine by 8-aminoadenine and guanine by 8-aminoguanine is analyzed. The presence of 8-aminoadenine and 8-aminoguanine stabilizes the parallel duplex structure. Binding of these oligonucleotides to their target polypyrimidine sequences to form the corresponding G,T-parallel triplex was not observed. Instead, when unmodified parallel-stranded duplexes were mixed with their polypyrimidine target, an interstrand Watson-Crick duplex was formed. As predicted by theoretical calculations parallel-stranded duplexes carrying 8-aminopurines did not bind to their target. The preference for the parallel-duplex over the Watson-Crick antiparallel duplex is attributed to the strong stabilization of the parallel duplex produced by the 8-aminopurines. Theoretical studies show that the isomorphism of the triads is crucial for the stability of the parallel triplex.

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Molecular simulations of lipid membrane partitioning and translocation by bacterial quorum sensing modulators

PLoS ONE ◽

10.1371/journal.pone.0246187 ◽

2021 ◽

Vol 16 (2) ◽

pp. e0246187

Author(s):

Tianyi Jin ◽

Samarthaben J. Patel ◽

Reid C. Van Lehn

Keyword(s):

Quorum Sensing ◽

Lipid Bilayers ◽

Lipid Membrane ◽

Computational Cost ◽

Md Simulations ◽

Umbrella Sampling ◽

Communication Process ◽

Free Energies ◽

Membrane Partitioning ◽

Solvent Model

Quorum sensing (QS) is a bacterial communication process mediated by both native and non-native small-molecule quorum sensing modulators (QSMs), many of which have been synthesized to disrupt QS pathways. While structure-activity relationships have been developed to relate QSM structure to the activation or inhibition of QS receptors, less is known about the transport mechanisms that enable QSMs to cross the lipid membrane and access intracellular receptors. In this study, we used atomistic MD simulations and an implicit solvent model, called COSMOmic, to analyze the partitioning and translocation of QSMs across lipid bilayers. We performed umbrella sampling at atomistic resolution to calculate partitioning and translocation free energies for a set of naturally occurring QSMs, then used COSMOmic to screen the water-membrane partition and translocation free energies for 50 native and non-native QSMs that target LasR, one of the LuxR family of quorum-sensing receptors. This screening procedure revealed the influence of systematic changes to head and tail group structures on membrane partitioning and translocation free energies at a significantly reduced computational cost compared to atomistic MD simulations. Comparisons with previously determined QSM activities suggest that QSMs that are least likely to partition into the bilayer are also less active. This work thus demonstrates the ability of the computational protocol to interrogate QSM-bilayer interactions which may help guide the design of new QSMs with engineered membrane interactions.

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An Efficient GaMD Multi-Level Enhanced Sampling Strategy: Application to Polarizable Force Fields Simulations of Large Biological Systems

10.33774/chemrxiv-2021-ggjfx-v3 ◽

2021 ◽

Author(s):

Fréderic Célerse ◽

Theo Jaffrelot-Inizan ◽

Louis Lagardère ◽

Olivier Adjoua ◽

Pierre Monmarché ◽

...

Keyword(s):

Molecular Dynamics ◽

Adaptive Sampling ◽

Sampling Strategy ◽

Umbrella Sampling ◽

Potential Of Mean Force ◽

Enhanced Sampling ◽

Polarizable Force Field ◽

Accelerated Molecular Dynamics ◽

Polarizable Force Fields ◽

Multi Level

We detail a novel multi-level enhanced sampling strategy grounded on Gaussian accelerated Molecular Dynamics (GaMD). First, we propose a GaMD multi-GPUs-accelerated implementation within the Tinker-HP molecular dynamics package. We then introduce the new "dual-water" mode and its use with the flexible AMOEBA polarizable force field. By adding harmonic boosts to the water stretching and bonding terms, it accelerates the solvent-solute interactions while enabling speedups thanks to the use of fast multiple--timestep integrators. To further reduce time-to-solution, we couple GaMD to Umbrella Sampling (US). The GaMD—US/dual-water approach is tested on the 1D Potential of Mean Force (PMF) of the CD2-CD58 system (168000 atoms) allowing the AMOEBA PMF to converge within 1 kcal/mol of the experimental value. Finally, Adaptive Sampling (AS) is added enabling AS-GaMD capabilities but also the introduction of the new Adaptive Sampling--US--GaMD (ASUS--GaMD) scheme. The highly parallel ASUS--GaMD setup decreases time to convergence by respectively 10 and 20 compared to GaMD--US and US.

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An Efficient GaMD Multi-Level Enhanced Sampling Strategy for Polarizable Force Fields Simulations of Large Biological Systems

10.33774/chemrxiv-2021-ggjfx ◽

2021 ◽

Author(s):

Fréderic Célerse ◽

Theo Jaffrelot-Inizan ◽

Louis Lagardère ◽

Olivier Adjoua ◽

Pierre Monmarché ◽

...

Keyword(s):

Adaptive Sampling ◽

Sampling Strategy ◽

Umbrella Sampling ◽

Potential Of Mean Force ◽

Enhanced Sampling ◽

Polarizable Force Field ◽

Accelerated Molecular Dynamics ◽

Polarizable Force Fields ◽

Solute Interactions ◽

Multi Level

We introduce a novel multi-level enhanced sampling strategy grounded on Gaussian accelerated Molecular Dynamics (GaMD). First, we propose a GaMD multi-GPUs -accelerated implementation within Tinker-HP. For the specific use with the flexible AMOEBA polarizable force field (PFF), we introduce the new "dual–water" GaMD mode. By adding harmonic boosts to the water stretching and bonding terms, it accelerates the solvent-solute interactions while enabling speedups with fast multiple–timestep integrators. To further reduce time-to-solution, we couple GaMD to Umbrella Sampling (US). The GaMD—US/dual–water approach is tested on the 1D Potential of Mean Force (PMF) of the CD2–CD58 system (168000 atoms) allowing the AMOEBA PMF to converge within 1 kcal/mol of the experimental value. Finally, Adaptive Sampling (AS) is added enabling AS–GaMD capabilities but also the introduction of the new Adaptive Sampling–US–GaMD (ASUS–GaMD) scheme. The highly parallel ASUS–GaMD setup decreases time to convergence by respectively 10 and 20 compared to GaMD–US and US.

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