scholarly journals Rigorous analysis of free solution glycosaminoglycan dynamics using simple, new tools

Glycobiology ◽  
2020 ◽  
Vol 30 (8) ◽  
pp. 516-527
Author(s):  
Balaji Nagarajan ◽  
Nehru Viji Sankaranarayanan ◽  
Umesh R Desai
Keyword(s):  
Force Fields ◽  
Protein Recognition ◽  
Water Molecules ◽  
Biological Functions ◽  
Computational Simulations ◽  
Rigorous Analysis ◽  
Protein Targets ◽  
End Distance ◽  
Heparan Sulfates ◽  
The Comparative Study

Abstract Heparin/heparan sulfates (H/HS) are ubiquitous biopolymers that interact with many proteins to induce a range of biological functions. Unfortunately, how these biopolymers recognize their preferred protein targets remain poorly understood. It is suggested that computational simulations offer attractive avenues but a number of challenges, e.g., difficulty of selecting a comprehensive force field, few simple tools to interpret data, among others, remain. This work addresses several such challenges so as to help ease the implementation and analysis of computational experiments. First, this work presents a rigorous comparison of two different recent force fields, CHARMM36 and GLYCAM06, for H/HS studies. Second, it introduces two new straightforward parameters, i.e., end-to-end distance and minimum volume enclosing ellipsoid, to understand the myriad conformational forms of oligosaccharides that evolve over time in water. Third, it presents an application to elucidate the number and nature of inter and intramolecular, nondirect bridging water molecules, which help stabilize unique forms of H/HS. The results show that nonspecialists can use either CHARMM36 or GLYCAM06 force fields because both gave comparable results, albeit with small differences. The comparative study shows that the HS hexasaccharide samples a range of conformations with nearly equivalent energies, which could be the reason for its recognition by different proteins. Finally, analysis of the nondirect water bridges across the dynamics trajectory shows their importance in stabilization of certain conformational forms, which may become important for protein recognition. Overall, the work aids nonspecialists employ computational studies for understanding the solution behavior of H/HS.

scholarly journals Novel Roles for the Sirtuin Deacylase SIRT5 in Normal Physiology and in Cancer

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 741-741
Author(s):  
David Lombard
Keyword(s):  
Mitochondrial Matrix ◽  
Genomic Integrity ◽  
Biological Functions ◽  
Protein Targets ◽  
Post Translational Modifications ◽  
Catalytic Activities ◽  
Cellular Processes ◽  
Specific Cancer ◽  
Cancer Types ◽  
Chromatin Biology

Abstract Sirtuins are NAD+-dependent deacylases that regulate diverse cellular processes such as metabolic homeostasis and genomic integrity. Mammals possess seven sirtuin family members, SIRT1-SIRT7, that display diverse subcellular localization patterns, catalytic activities, protein targets, and biological functions. Three sirtuins, SIRT3, SIRT4, and SIRT5, are primarily located in the mitochondrial matrix. SIRT5 is a very inefficient deacetylase, instead removing negatively charged post-translational modifications (succinyl, glutaryl, and malonyl groups) from lysines of its target proteins, in mitochondria and throughout the cell. SIRT5 plays only modest known roles in normal physiology, with its major functions occurring in the heart under stress conditions. In contrast, in specific cancer types, including melanoma, we have identified a major pro-survival role for SIRT5. We have traced this function of SIRT5 to novel roles for this protein in regulating chromatin biology. New insights into mechanisms of SIRT5 action in cancer, and in normal myocardium, will be discussed.

Computational approaches for drug discovery against trypanosomatid-caused diseases

Parasitology ◽  
2020 ◽  
Vol 147 (6) ◽  
pp. 611-633 ◽  
Author(s):  
Claudio A. Pereira ◽  
Melisa Sayé ◽  
Chantal Reigada ◽  
Ariel M. Silber ◽  
Guillermo R. Labadie ◽  
...  
Keyword(s):  
Selection Criteria ◽  
Disease Burden ◽  
Neglected Tropical Diseases ◽  
Drug Repurposing ◽  
New Drugs ◽  
Computational Simulations ◽  
Protein Targets ◽  
Pharmacologically Active ◽  
Pharmacologically Active Compounds ◽  
Research Investments

AbstractDuring three decades, only about 20 new drugs have been developed for malaria, tuberculosis and all neglected tropical diseases (NTDs). This critical situation was reached because NTDs represent only 10% of health research investments; however, they comprise about 90% of the global disease burden. Computational simulations applied in virtual screening (VS) strategies are very efficient tools to identify pharmacologically active compounds or new indications for drugs already administered for other diseases. One of the advantages of this approach is the low time-consuming and low-budget first stage, which filters for testing experimentally a group of candidate compounds with high chances of binding to the target and present trypanocidal activity. In this work, we review the most common VS strategies that have been used for the identification of new drugs with special emphasis on those applied to trypanosomiasis and leishmaniasis. Computational simulations based on the selected protein targets or their ligands are explained, including the method selection criteria, examples of successful VS campaigns applied to NTDs, a list of validated molecular targets for drug development and repositioned drugs for trypanosomatid-caused diseases. Thereby, here we present the state-of-the-art of VS and drug repurposing to conclude pointing out the future perspectives in the field.

Characterizing the Water Wire in the Gramicidin Channel Found by Monte Carlo Sampling Using Continuum Electrostatics and in Molecular Dynamics Trajectories with Conventional or Polarizable Force Fields

2020 ◽  
pp. 1-20
Author(s):  
Yingying Zhang ◽  
Kamran Haider ◽  
Divya Kaur ◽  
Van A. Ngo ◽  
Xiuhong Cai ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Dipole Moment ◽  
Electrostatic Interactions ◽  
Hybrid Methods ◽  
Force Fields ◽  
Proton Channel ◽  
Water Molecules ◽  
Implicit Solvent ◽  
Continuum Electrostatics ◽  
Hydrogen Bond Networks

Water molecules play a key role in all biochemical processes. They help define the shape of proteins, and they are reactant or product in many reactions and are released as ligands are bound. They facilitate the transfer of protons through transmembrane proton channel, pump and transporter proteins. Continuum electrostatics (CE) force fields used by program Multiconformation CE (MCCE) capture electrostatic interactions in biomolecules with an implicit solvent, which captures the averaged solvent water equilibrium properties. Hybrid CE methods can use explicit water molecules within the protein surrounded by implicit solvent. These hybrid methods permit the study of explicit hydrogen bond networks within the protein and allow analysis of processes such as proton transfer reactions. Yet hybrid CE methods have not been rigorously tested. Here, we present an explicit treatment of water molecules in the Gramicidin A (gA) channel using MCCE and compare the resulting distributions of water molecules and key hydration features against those obtained with explicit solvent Molecular Dynamics (MD) simulations with the nonpolarizable CHARMM36 and polarizable Drude force fields. CHARMM36 leads to an aligned water wire in the channel characterized by a large absolute net water dipole moment; the MCCE and Drude analysis lead to a small net dipole moment as the water molecules change orientation within the channel. The correct orientation is not as yet known, so these calculations identify an open question.

ABEEMσπ FLUCTUATING CHARGE FORCE FIELD APPLIED TO ALANINE DIPEPTIDE AND ALANINE DIPEPTIDE–WATER SYSTEMS

2010 ◽  
Vol 09 (supp01) ◽  
pp. 77-97 ◽  
Author(s):  
CUI LIU ◽  
DONG-XIA ZHAO ◽  
ZHONG-ZHI YANG
Keyword(s):  
Force Fields ◽  
Lone Pair ◽  
Water Systems ◽  
Water Molecules ◽  
Hydration Water ◽  
Electronegativity Equalization Method ◽  
Lone Pair Electrons ◽  
Alanine Dipeptide ◽  
Packing Effects ◽  
Atom Bond

Atom-bond electronegativity equalization method at σπ level fused into molecular mechanics (ABEEMσπ/MM) divides the bond regions into σ and π bond regions on the basis of previous ABEEM/MM. It may suitably reflect intramolecular and intermolecular interaction and polarization. The fitting function k H-bond in the hydrogen bond (HB) interaction region increases the capability of ABEEMσπ/MM to simulate the hydration. Hydration of alanine dipeptide (AD) in aqueous solution is determined by the intramolecular and intermolecular HBs and the competition among the molecular packing effects. The acceptor molecule in HB complex contains at least one pair of lone pair electrons, sometimes contains π bonds, whose orientations directly effect the orientation of HBs. Therefore, ABEEMσπ/MM has obviously predominance to discuss the AD and AD–water systems, which contain many lone pair electrons, π bonds, and abundant HB nets. Properties of six AD conformers, clusters AD +( H2O )1–4 obtained from ABEEMσπ/MM agree well with the results of experiments, ab initio and other force fields. Structural and dynamical properties of the hydration water molecules have just embodied that the ABEEMσπ/MM gives correct hydration description relative to other force fields.

Structures of the complexes of peanut lectin with methyl-β-galactose and N-acetyllactosamine and a comparative study of carbohydrate binding in Gal/GalNAc-specific legume lectins

1999 ◽  
Vol 55 (8) ◽  
pp. 1375-1382 ◽  
Author(s):  
R. Ravishankar ◽  
K. Suguna ◽  
A. Surolia ◽  
M. Vijayan
Keyword(s):  
Comparative Study ◽  
Water Molecules ◽  
Carbohydrate Binding ◽  
Hydroxyl Groups ◽  
Peanut Lectin ◽  
Structural Explanation ◽  
Sugar Ring ◽  
Ordered Water ◽  
The Comparative Study

The crystal structures of complexes of peanut lectin with methyl-β-galactose and N-acetyllactosamine have been determined at 2.8 and 2.7 Å, respectively. These, and the complexes involving lactose and the T-antigenic disaccharide reported previously, permit a detailed characterization of peanut-lectin–carbohydrate association and the role of water molecules therein. The water molecules in the combining site are substantially conserved in the four complexes. The role of interacting sugar hydroxyl groups, when absent, are often mimicked by ordered water molecules not only at the primary combining site, but also at the site of the second sugar ring. The similarity of peanut-lectin–sugar interactions with those in other galactose/N-acetylgalactosamine-specific lectins also extend to a substantial degree to water bridges. The comparative study provides a structural explanation for the exclusive specificity of peanut lectin for galactose at the monosaccharide level, compared with that of the other lectins for galactose as well as N-acetylgalactosamine. The complexes also provide a qualitative structural rationale for differences in the strengths of binding of peanut lectin to different sugars.

Internal and external force fields and normal vibrations of the water molecules in Ba(ClO3)2.H2O and K2C2O4.H2O

1979 ◽  
Vol 52 ◽  
pp. 95-105 ◽  
Author(s):  
A. Eriksson ◽  
M.A. Hussein ◽  
B. Berglund ◽  
J. Tegenfeldt ◽  
J. Lindgren
Keyword(s):  
External Force ◽  
Force Fields ◽  
Water Molecules ◽  
Normal Vibrations

Heparan sulfate glycomics: towards systems biology strategies

2010 ◽  
Vol 38 (5) ◽  
pp. 1356-1360 ◽  
Author(s):  
Jeremy E. Turnbull
Keyword(s):  
Systems Biology ◽  
Cell Surface ◽  
Heparan Sulfate ◽  
Biological Functions ◽  
Combined Application ◽  
Cellular Events ◽  
Structure Activity ◽  
Future Potential ◽  
Heparan Sulfates ◽  
Molecular Code

HSs (heparan sulfates) are a complex family of cell-surface and matrix polysaccharides that have diverse biological functions, underpinned by structurally diverse patterns of backbone chain modification, especially by sulfate groups. These variant structures represent a molecular code, the ‘heparanome’, that confers the ability to interact selectively with a wide interactome of proteins, the ‘heparactome’, and thereby influence a network of cellular events. It is becoming increasingly apparent that understanding the structure–activity relationships of these enigmatic molecules requires the development of a holistic systems biology view of their structure and interactions. In the present paper, I describe some of the new tools available to realize this strategy, and discuss the future potential for the combined application of glycomics and other ‘-omics’ approaches to define the molecular code of the heparanome.

scholarly journals Biological Functions of Heparan Sulfates.

1998 ◽  
Vol 10 (52) ◽  
pp. 193-210 ◽  
Author(s):  
K. Mishra-Gorur ◽  
L. M. Delmolino ◽  
J. J. Castellot Jr.
Keyword(s):  
Biological Functions ◽  
Heparan Sulfates

scholarly journals Synthetic mimetics of protein secondary structure domains

2010 ◽  
Vol 368 (1914) ◽  
pp. 989-1008 ◽  
Author(s):  
Nathan T. Ross ◽  
William P. Katt ◽  
Andrew D. Hamilton
Keyword(s):  
Secondary Structure ◽  
Functional Groups ◽  
Biological Systems ◽  
Protein Secondary Structure ◽  
Protein Recognition ◽  
Structural Elements ◽  
Biological Functions ◽  
Major Focus ◽  
The Past ◽  
Secondary Structural Elements

Proteins modulate the majority of all biological functions and are primarily composed of highly organized secondary structural elements such as helices, turns and sheets. Many of these functions are affected by a small number of key protein–protein contacts, often involving one or more of these well-defined structural elements. Given the ubiquitous nature of these protein recognition domains, their mimicry by peptidic and non-peptidic scaffolds has become a major focus of contemporary research. This review examines several key advances in secondary structure mimicry over the past several years, particularly focusing upon scaffolds that show not only promising projection of functional groups, but also a proven effect in biological systems.

Characterizing the water wire in the Gramicidin channel found by Monte Carlo sampling using continuum electrostatics and in molecular dynamics trajectories with conventional or polarizable force fields

2020 ◽  
pp. 2042001
Author(s):  
Yingying Zhang ◽  
Kamran Haider ◽  
Divya Kaur ◽  
Van A. Ngo ◽  
Xiuhong Cai ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Dipole Moment ◽  
Electrostatic Interactions ◽  
Hybrid Methods ◽  
Force Fields ◽  
Proton Channel ◽  
Water Molecules ◽  
Implicit Solvent ◽  
Continuum Electrostatics ◽  
Hydrogen Bond Networks

Water molecules play a key role in all biochemical processes. They help define the shape of proteins, and they are reactant or product in many reactions and are released as ligands are bound. They facilitate the transfer of protons through transmembrane proton channel, pump and transporter proteins. Continuum electrostatics (CE) force fields used by program Multiconformation CE (MCCE) capture electrostatic interactions in biomolecules with an implicit solvent, which captures the averaged solvent water equilibrium properties. Hybrid CE methods can use explicit water molecules within the protein surrounded by implicit solvent. These hybrid methods permit the study of explicit hydrogen bond networks within the protein and allow analysis of processes such as proton transfer reactions. Yet hybrid CE methods have not been rigorously tested. Here, we present an explicit treatment of water molecules in the Gramicidin A (gA) channel using MCCE and compare the resulting distributions of water molecules and key hydration features against those obtained with explicit solvent Molecular Dynamics (MD) simulations with the nonpolarizable CHARMM36 and polarizable Drude force fields. CHARMM36 leads to an aligned water wire in the channel characterized by a large absolute net water dipole moment; the MCCE and Drude analysis lead to a small net dipole moment as the water molecules change orientation within the channel. The correct orientation is not as yet known, so these calculations identify an open question.

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