scholarly journals Optimization of an in silico protocol to characterize membrane PAINS

2021 ◽  
Author(s):  
Pedro R. Magalhães ◽  
Pedro B. P. S. Reis ◽  
Diogo Vila-Viçosa ◽  
Miguel Machuqueiro ◽  
Bruno L. Victor
Keyword(s):  
Lipid Bilayers ◽  
Early Identification ◽  
In Silico ◽  
Reference Method ◽  
Md Simulations ◽  
Umbrella Sampling ◽  
Membrane Thickness ◽  
The Us ◽  
Distinct Membrane ◽  
Assay Interference

Membrane Pan-Assay INterference compoundS (PAINS) are a class of molecules that interact non-specifically with lipid bilayers and alter their physicochemical properties. An early identification of these compounds avoids chasing false leads and the needless waste of time and resources in drug discovery campaigns. In this work, we optimized an in silico protocol based on umbrella sampling (US)/MD simulations to discriminate between compounds with different membrane PAINS behavior. We showed that the method is quite sensitive to membrane thickness fluctuations, which was mitigated by changing the US-reference position to the P-atoms of the closest interacting monolayer. The computational efficiency was improved further by decreasing the number of umbrellas and adjusting their strength and position in our US scheme. The ISDM-calculated membrane permeability coefficients confirmed that resveratrol and curcumin have distinct membrane PAINS characteristics and indicate a misclassification of nothofagin in a previous work. Overall, we have presented here a promising in silico protocol which can be adopted as a future reference method to identify membrane PAINS.

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

PLoS ONE ◽  
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.

scholarly journals Membrane Catalysed Formation of Nucleotide Clusters and Its Role in the Origins of Life

2020 ◽  
Author(s):  
Rajlaxmi Saha ◽  
Prathyush Poduval ◽  
Jayashree Nagesh ◽  
Anand Srivastava
Keyword(s):  
Mathematical Model ◽  
Random Walk ◽  
Unique Feature ◽  
Md Simulations ◽  
Umbrella Sampling ◽  
Early Earth ◽  
Mineral Surface ◽  
Hydration And Dehydration ◽  
Distinct Membrane

<div>Non-enzymatic polymerisation explained how life could assemble spontaneously on the early Earth. Prior research has discovered that the non-enzymatic polymerisation can be mediated by various environmental settings, most widely accepted are the reactions driven by the cycles of hydration and dehydration and organising matrices such as clay, salt, membranes and mineral surface. Membranes have a unique feature which prepares it as a sensitive organising matrix, as compared to mineral surface and clay, which transforms its phase with small changes in temperature, hydration and composition of lipids. Multi-component membranes can show phase separation where two or more distinct phases can co-exist. To the best of our knowledge, this is for the fi?rst time the influence of different phases of the membrane in the nucleotide organisation and polymerisation in a simulated prebiotic setting in this work have been explored. This study encompasses the energetics of inserting a mononucleotide, UMP, in distinct membrane settings which is probed utilising the PMF. The preferential partitioning of UMP is also investigated; which is coupled to the location of the insertion and the composition of the PSM/DOPC/Chol membranes. Combined with umbrella-sampling calculations, AA-MD simulations were performed to estimate the role of the</div><div>monophasic and diphasic membrane in modifying the behaviour of UMPs and their clustering mechanism. A mathematical model was also developed based on lattice model and random walk and some of the parameters were trained from the AA-MD simulations. The results indicated that the membranes were capable of concentrating nucleotides and organised into anisotropic clusters, and the thermodynamic studies along with mathematical model showed that it had a sharp preference for the Lo/Ld domain interface for clustering.</div>

scholarly journals Membrane Catalysed Formation of Nucleotide Clusters and Its Role in the Origins of Life

2020 ◽  
Author(s):  
Rajlaxmi Saha ◽  
Prathyush Poduval ◽  
Jayashree Nagesh ◽  
Anand Srivastava
Keyword(s):  
Mathematical Model ◽  
Random Walk ◽  
Unique Feature ◽  
Md Simulations ◽  
Umbrella Sampling ◽  
Early Earth ◽  
Mineral Surface ◽  
Hydration And Dehydration ◽  
Distinct Membrane

<div>Non-enzymatic polymerisation explained how life could assemble spontaneously on the early Earth. Prior research has discovered that the non-enzymatic polymerisation can be mediated by various environmental settings, most widely accepted are the reactions driven by the cycles of hydration and dehydration and organising matrices such as clay, salt, membranes and mineral surface. Membranes have a unique feature which prepares it as a sensitive organising matrix, as compared to mineral surface and clay, which transforms its phase with small changes in temperature, hydration and composition of lipids. Multi-component membranes can show phase separation where two or more distinct phases can co-exist. To the best of our knowledge, this is for the fi?rst time the influence of different phases of the membrane in the nucleotide organisation and polymerisation in a simulated prebiotic setting in this work have been explored. This study encompasses the energetics of inserting a mononucleotide, UMP, in distinct membrane settings which is probed utilising the PMF. The preferential partitioning of UMP is also investigated; which is coupled to the location of the insertion and the composition of the PSM/DOPC/Chol membranes. Combined with umbrella-sampling calculations, AA-MD simulations were performed to estimate the role of the</div><div>monophasic and diphasic membrane in modifying the behaviour of UMPs and their clustering mechanism. A mathematical model was also developed based on lattice model and random walk and some of the parameters were trained from the AA-MD simulations. The results indicated that the membranes were capable of concentrating nucleotides and organised into anisotropic clusters, and the thermodynamic studies along with mathematical model showed that it had a sharp preference for the Lo/Ld domain interface for clustering.</div>

Appraisal of the role of In silico Methods in Pyrazole based drug design

2020 ◽  
Vol 20 ◽  
Author(s):  
Smriti Sharma ◽  
Vinayak Bhatia
Keyword(s):  
Drug Design ◽  
In Silico ◽  
Md Simulations ◽  
Quantitative Structure Activity Relationship ◽  
Field Analysis ◽  
Computational Techniques ◽  
Neuroprotective Drugs ◽  
Pharmacological Potential ◽  
Available Information ◽  
Anti Fungal

: Pyrazole and its derivatives are a pharmacologically significant active scaffold that have innumerable physiological and pharmacological activities. They can be very good targets for the discovery of novel anti-bacterial, anticancer, anti-inflammatory, anti-fungal, anti-tubercular, antiviral, antioxidant, antidepressant, anti-convulsant and neuroprotective drugs. This review focuses on the importance of in silico manipulations of pyrazole and its derivatives for medicinal chemistry. The authors have discussed currently available information on the use of computational techniques like molecular docking, structure-based virtual screening (SBVS), molecular dynamics (MD) simulations, quantitative structure activity relationship (QSAR), comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) to drug design using pyrazole moieties. Pyrazole based drug design is mainly dependent on the integration of experimental and computational approaches. The authors feel that more studies need to be done to fully explore the pharmacological potential of the pyrazole moiety and in silico method can be of great help.

In Silico and in Vitro Evaluation of Deamidation Effects on the Stability of the Fusion Toxin DAB389IL-2

2019 ◽  
Vol 16 (4) ◽  
pp. 307-313 ◽  
Author(s):  
Nasrin Zarkar ◽  
Mohammad Ali Nasiri Khalili ◽  
Fathollah Ahmadpour ◽  
Sirus Khodadadi ◽  
Mehdi Zeinoddini
Keyword(s):  
In Silico ◽  
Catalytic Domain ◽  
Md Simulations ◽  
Special Importance ◽  
Native Form ◽  
Vitro Experiment ◽  
In Vitro Experiment ◽  
Pharmaceutical Protein ◽  
The Stability

Background: DAB389IL-2 (Denileukin diftitox) as an immunotoxin is a targeted pharmaceutical protein and is the first immunotoxin approved by FDA. It is used for the treatment of various kinds of cancer such as CTCL lymphoma, melanoma, and Leukemia but among all of these, treatment of CTCL has special importance. DAB389IL-2 consists of two distinct parts; the catalytic domain of Diphtheria Toxin (DT) that genetically fused to the whole IL-2. Deamidation is the most important reaction for chemical instability of proteins occurs during manufacture and storage. Deamidation of asparagine residues occurs at a higher rate than glutamine residues. The structure of proteins, temperature and pH are the most important factors that influence the rate of deamidation. Methods: Since there is not any information about deamidation of DAB389IL-2, we studied in silico deamidation by Molecular Dynamic (MD) simulations using GROMACS software. The 3D model of fusion protein DAB389IL-2 was used as a template for deamidation. Then, the stability of deamidated and native form of the drug was calculated. Results: The results of MD simulations were showed that the deamidated form of DAB389IL-2 is more unstable than the normal form. Also, deamidation was carried by incubating DAB389IL-2, 0.3 mg/ml in ammonium hydrogen carbonate for 24 h at 37o C in order to in vitro experiment. Conclusion: The results of in vitro experiment were confirmed outcomes of in silico study. In silico and in vitro experiments were demonstrated that DAB389IL-2 is unstable in deamidated form.

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

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.

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

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.

scholarly journals Effect of hydrophobically modified PEO polymers (PEO-dodecyl) on oil/water microemulsion properties: in vitro and in silico investigations

RSC Advances ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 7059-7069
Author(s):  
M. Khatouri ◽  
R. Ahfir ◽  
M. Lemaalam ◽  
S. El Khaoui ◽  
A. Derouiche ◽  
...  
Keyword(s):  
Integral Equations ◽  
In Silico ◽  
Md Simulations ◽  
Hydrophobically Modified ◽  
Oil Water

In this work, we study the effect of grafted PEO-dodecyl co-polymers on the decane/water microemulsions properties. For this purpose, we combined the MD simulations, the OZ integral equations resolved using the HNC closure, and SANS experiments.

scholarly journals Identification of rare Lewis oligosaccharide conformers in aqueous solution using enhanced sampling molecular dynamics

2017 ◽  
Author(s):  
Irfan Alibay ◽  
Kepa K. Burusco ◽  
Neil J. Bruce ◽  
Richard A. Bryce
Keyword(s):  
Molecular Dynamics ◽  
Aqueous Solution ◽  
Md Simulations ◽  
Umbrella Sampling ◽  
Biological Action ◽  
Sialyl Lewis X ◽  
Enhanced Sampling ◽  
Sialyl Lewis ◽  
Aqueous Solvent ◽  
A Minor

<p>Determining the conformations accessible to carbohydrate ligands in aqueous solution is important for understanding their biological action. In this work, we evaluate the conformational free energy surfaces of Lewis oligosaccharides in explicit aqueous solvent using a multidimensional variant of the swarm-enhanced sampling molecular dynamics (msesMD) method; we compare with multi-microsecond unbiased MD simulations, umbrella sampling and accelerated MD approaches. For the sialyl Lewis A tetrasaccharide, msesMD simulations in aqueous solution predict conformer landscapes in general agreement with the other biased methods and with triplicate unbiased 10 ms trajectories; these simulations find a predominance of closed conformer and a range of low occupancy open forms. The msesMD simulations also suggest closed-to-open transitions in the tetrasaccharide are facilitated by changes in ring puckering of its GlcNAc residue away from the <sup>4</sup>C<sub>1</sub> form, in line with previous work. For sialyl Lewis X tetrasaccharide, msesMD simulations predict a minor population of an open form in solution, corresponding to a rare lectin-bound pose observed crystallographically. Overall, from comparison with biased MD calculations, we find that triplicate 10 ms unbiased MD simulations may not be enough to fully sample glycan conformations in aqueous solution. However, the computational efficiency and intuitive approach of the msesMD method suggest potential for its application in glycomics as a tool for analysis of oligosaccharide conformation.</p>

Diffusion of atomic oxygen relevant to water formation in amorphous interstellar ices

2014 ◽  
Vol 168 ◽  
pp. 205-222 ◽  
Author(s):  
Myung Won Lee ◽  
Markus Meuwly
Keyword(s):  
Electrostatic Interactions ◽  
Atomic Oxygen ◽  
Md Simulations ◽  
Umbrella Sampling ◽  
Chemical Mechanism ◽  
Amorphous Ice ◽  
Migration Barriers ◽  
Water Formation ◽  
Interstellar Ices ◽  
Migration Pathways

Molecular dynamics (MD) simulations together with accurate physics-based force fields are employed to determine the mobility of atomic oxygen in amorphous ice at low temperatures, characteristic for conditions in interstellar ices. From the simulations it is found that the mobility of atomic oxygen ranges from 60 to 480 Å2 ns−1 in amorphous ice at temperatures between 50 and 200 K. Hence, the simulations establish that atomic oxygen is mobile to a certain degree and a chemical mechanism for water formation involving oxygen mobility is a realistic scenario. This is also confirmed by the computed migration barriers for oxygen diffusion by multiple umbrella sampling simulations, which yield barriers for diffusion in the range of 0.7–1.9 kcal mol−1. The physics-based force field – based on a multipolar expansion of the electrostatic interactions – yields more pronounced energetics for oxygen migration pathways compared to the conventional point-charge models employed in typical simulations. Once formed, the computed solvation free energy suggests that atomic oxygen thermodynamically prefers to be localized inside amorphous ice and is available for chemical reaction, which may be relevant to water formation in and on grains.

Sign in / Sign up

Export Citation Format

Share Document