Predicting stabilizing mutations in proteins using Poisson–Boltzmann based models: study of unfolded state ensemble models and development of a successful binary classifier based on residue interaction energies

2015 ◽  
Vol 17 (46) ◽  
pp. 31044-31054 ◽  
Author(s):  
Jorge Estrada ◽  
Pablo Echenique ◽  
Javier Sancho
Keyword(s):  
Interaction Energies ◽  
Binary Classifier ◽  
Ensemble Models ◽  
Residue Interaction ◽  
Unfolded State ◽  
State Ensemble ◽  
Poisson Boltzmann ◽  
The Stability

In many cases the stability of a protein has to be increased to permit its biotechnological use.

scholarly journals D614G substitution enhances the stability of trimeric SARS-CoV-2 spike protein

2020 ◽  
Author(s):  
Arangasamy Yazhini ◽  
Das Swayam Prakash Sidhanta ◽  
Narayanaswamy Srinivasan
Keyword(s):  
Thermodynamic Stability ◽  
Energy Difference ◽  
Spike Protein ◽  
Interaction Energies ◽  
Free Energy Difference ◽  
Residue Interaction ◽  
Ancestral Virus ◽  
Glycine Substitution ◽  
Favourable Environment ◽  
The Stability

AbstractSARS-CoV-2 spike protein with D614G substitution has become the dominant variant in the ongoing COVID-19 pandemic. Several studies to characterize the new virus expressing G614 variant show that it exhibits increased infectivity compared to the ancestral virus having D614 spike protein. Here, using in-silico mutagenesis and energy calculations, we analyzed inter-residue interaction energies and thermodynamic stability of the dominant (G614) and the ancestral (D614) variants of spike protein trimer in ‘closed’ and ‘partially open’ conformations. We find that the local interactions mediated by aspartate at the 614th position are energetically frustrated and create unfavourable environment. Whereas, glycine at the same position confers energetically favourable environment and strengthens intra-as well as inter-protomer association. Such changes in the local interaction energies enhance the thermodynamic stability of the spike protein trimer as free energy difference (ΔΔG) upon glycine substitution is −2.6 kcal/mol for closed conformation and −2.0 kcal/mol for open conformation. Our results on the structural and energetic basis of enhanced stability hint that G614 may confer increased availability of functional form of spike protein trimer and consequent in higher infectivity than the D614 variant.

Examining sharp restart in a Monte Carlo method for the linearized Poisson–Boltzmann equation

2020 ◽  
Vol 26 (3) ◽  
pp. 223-244
Author(s):  
W. John Thrasher ◽  
Michael Mascagni
Keyword(s):  
Monte Carlo ◽  
Free Energy ◽  
Monte Carlo Algorithm ◽  
Significant Bias ◽  
Poisson Boltzmann ◽  
Electrostatic Free Energy ◽  
Poisson Boltzmann Equation ◽  
The Stability ◽  
Potential Methods ◽  
The Individual

AbstractIt has been shown that when using a Monte Carlo algorithm to estimate the electrostatic free energy of a biomolecule in a solution, individual random walks can become entrapped in the geometry. We examine a proposed solution, using a sharp restart during the Walk-on-Subdomains step, in more detail. We show that the point at which this solution introduces significant bias is related to properties intrinsic to the molecule being examined. We also examine two potential methods of generating a sharp restart point and show that they both cause no significant bias in the examined molecules and increase the stability of the run times of the individual walks.

scholarly journals High stability of trehalose/maltose binding protein fromThermococcus litoralismakes it a good candidate as a sensitive element in biosensor systems for sugar control

2010 ◽  
Vol 24 (3-4) ◽  
pp. 349-353 ◽  
Author(s):  
Olga I. Povarova ◽  
Olga V. Stepanenko ◽  
Anna I. Sulatskaya ◽  
Irina M. Kuznetsova ◽  
Konstantin K. Turoverov ◽  
...  
Keyword(s):  
Free Energy ◽  
Sensitive Element ◽  
High Stability ◽  
Binding Protein ◽  
Maltose Binding Protein ◽  
Thermococcus Litoralis ◽  
Thermophilic Archaeon ◽  
Unfolded State ◽  
The Stability ◽  
Innate Ability

Fluorescence and circular dichroism in far-UV region were used to study the stability of trehalose/maltose binding protein (TMBP) from hyper thermophilic archaeonThermococcus litoralisand its complex with glucose (TMBP/Glc). The evaluation of difference between free energy of native and unfolded state for TMBP and TMBP/Glc showed that both of them are several times higher than that of proteins from mesophilic organisms. Due to the high stability and innate ability to bind glucose this protein is a good candidate as a sensitive element in biosensor systems for sugar control.

Effects of the Difference in the Unfolded-state Ensemble on the Folding of Escherichia coli Dihydrofolate Reductase

2003 ◽  
Vol 329 (4) ◽  
pp. 779-791 ◽  
Author(s):  
Munehito Arai ◽  
Mikio Kataoka ◽  
Kunihiro Kuwajima ◽  
C.Robert Matthews ◽  
Masahiro Iwakura
Keyword(s):  
Escherichia Coli ◽  
Dihydrofolate Reductase ◽  
Unfolded State ◽  
State Ensemble ◽  
The Difference

scholarly journals Molecular Interactions of Renin with Chikusetsusaponin IV and Momordin IIc

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Hai-Ling Zhang ◽  
Gui-Lan Zhu ◽  
Xiao-Tian Chen
Keyword(s):  
Hydrogen Bonding ◽  
Binding Sites ◽  
Driving Forces ◽  
Hydrophobic Interactions ◽  
Hydrophobic Effect ◽  
Energy Calculation ◽  
Total Binding Energy ◽  
Interaction Energies ◽  
Amino Acid Residues ◽  
Poisson Boltzmann

The paper dealt with the molecular mechanism for the binding sites and driving forces of renin with chikusetsusaponin IV and momordin IIc by means of molecular docking and free energy calculation based on the crystal structure. The result showed that renin and the saponins fit well. As shown by LigPlot + software analyzing the hydrogen bonding and hydrophobic effect between renin and the saponins, the amino acid residues such as Ser230, Tyr85, and Tyr201 form the hydrogen bonds, with S3sp, S3, and S2′ being the active pockets. In addition, there are relatively strong hydrophobic interactions of renin with saponins in S3sp, S3, S2, S1, S1′, and S2′, with Gly228, Val36, Ala229, Gln19, Met303, Gln135, Ser41, Ile137, Asp38, Arg82, and Tyr83 being the key amino acids. The dynamics reached equilibration after about 1000 ps simulation with average root-mean-square deviations of 0.222 nm and 0.217 nm. The molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) yielded −1.10812 kcal/mol and −39.0587 kcal/mol total binding energy for the two complexes, respectively, which were primarily contributed by electrostatic and van der Waals interaction energies, and the binding was strongly unfavored by polar solvation energy, a further confirmation that momordin IIc has stronger hydrogen bonding and hydrophobic effect in the inhibition of renin than the chikusetsusaponin IV.

COMPUTATIONAL STUDY FOR BINDING OF OSCILLARIN TO HUMAN α-THROMBIN

2009 ◽  
Vol 08 (04) ◽  
pp. 551-560 ◽  
Author(s):  
EMILIA L. WU ◽  
KELI HAN ◽  
JOHN Z. H. ZHANG
Keyword(s):  
Computational Study ◽  
Quantitative Information ◽  
Drug Binding ◽  
Dynamics Simulation ◽  
Marine Natural Product ◽  
Interaction Energies ◽  
Binding Interaction ◽  
Dft Methods ◽  
Ligand Interaction ◽  
Residue Interaction

Quantum mechanical calculation and molecular dynamics simulation have been carried out to study binding of Oscillarin (OSC), an antithrombotic marine natural product to human α-thrombin. The binding interaction energies between the inhibitor and individual protein fragments are calculated using a combination of HF and DFT methods. Study shows that the strong binding of OSC to Asp189, Ser214, Trp215, Gly216, and Gly219 is the primary mechanism of drug binding to thrombin. The individual residue–ligand interaction energies provide detailed quantitative information about specific residue interaction with the ligand that should be extremely useful to our understanding of the molecular nature of protein–ligand binding.

scholarly journals L1STABILITY FOR THE VLASOV–POISSON–BOLTZMANN SYSTEM AROUND VACUUM

2006 ◽  
Vol 16 (09) ◽  
pp. 1505-1526 ◽  
Author(s):  
RENJUN DUAN ◽  
MEI ZHANG ◽  
CHANGJIANG ZHU
Keyword(s):  
Existence Theory ◽  
Classical Solutions ◽  
Hard Sphere Model ◽  
Sphere Model ◽  
Small Initial Data ◽  
Dimensional Phase Space ◽  
Nonlinear Functionals ◽  
Poisson Boltzmann ◽  
The Stability ◽  
Hard Potentials

Based on the global existence theory of the Vlasov–Poisson–Boltzmann system around vacuum in the N-dimensional phase space, in this paper, we prove the uniform L1stability of classical solutions for small initial data when N ≥ 4. In particular, we show that the stability can be established directly for the soft potentials, while for the hard potentials and hard sphere model it is obtained through the construction of some nonlinear functionals. These functionals thus generalize those constructed by Ha for the case without force to capture the effect of the force term on the time evolution of solutions. In addition, the local-in-time L1stability is also obtained for the case of N = 3.

Pressure- and temperature-induced unfolding studies: thermodynamics of core hydrophobicity and packing of ribonuclease A

2006 ◽  
Vol 387 (3) ◽  
pp. 285-296 ◽  
Author(s):  
Josep Font ◽  
Antoni Benito ◽  
Joan Torrent ◽  
Reinhard Lange ◽  
Marc Ribó ◽  
...  
Keyword(s):  
Hydrophobic Interactions ◽  
Rnase A ◽  
Van Der Waals Interactions ◽  
Hydrophobic Core ◽  
Experimental Conditions ◽  
Unfolded State ◽  
Different Temperatures ◽  
Methylene Groups ◽  
The Stability ◽  
Core Packing

Abstract In this work we demonstrate that heat and pressure induce only slightly different energetic changes in the unfolded state of RNase A. Using pressure and temperature as denaturants on a significant number of variants, and by determining the free energy of unfolding at different temperatures, we estimated the stability of variants unable to complete the unfolding transition owing to the experimental conditions required for pressure experiments. The overall set of results allowed us to map the contributions to stability of the hydrophobic core residues of RNase A, with the positions most critical for stability being V54, V57, I106 and V108. We also show that the stability differences can be attributed to both hydrophobic interactions and packing density with an equivalent energetic magnitude. The main hydrophobic core of RNase A is tightly packed, as shown by the small-to-large and isosteric substitutions. In addition, we found that large changes in the number of methylene groups have non-additive positive stability interaction energies that are consistent with exquisite tight core packing and rearrangements of van der Waals' interactions in the protein interior, even after drastic deleterious substitutions.

scholarly journals Quinary interactions with an unfolded state ensemble

2017 ◽  
Vol 26 (9) ◽  
pp. 1698-1703 ◽  
Author(s):  
Rachel D. Cohen ◽  
Gary J. Pielak
Keyword(s):  
Unfolded State ◽  
State Ensemble

scholarly journals Nanoparticles Mediated Protein Stability in Comparison with Osmolytes: in vivo Approach

2021 ◽  
Vol 33 (6) ◽  
pp. 1433-1438
Author(s):  
R. Verma ◽  
N. Singh ◽  
P. Chaudhuri (Chattopadhyay)
Keyword(s):  
Gold Nanoparticles ◽  
Dihydrofolate Reductase ◽  
Three Dimensional ◽  
Cellular Level ◽  
Dimensional Structure ◽  
Important Group ◽  
Unfolded State ◽  
The Status ◽  
The Stability

The native three-dimensional structure of protein is quite unstable under critical destabilizing conditions. In order to enhance the stability and activity for a proper folded environment of a protein, many stabilizing materials are added such as nanoparticles and osmolytes to an unfolded state of protein. Osmolytes are the important group of molecules which are engaged by the cell as an adaption in the severe conditions. In this communication, a comparative in vivo study is reported for imparting the status of stability and folding ability of zebrafish dihydrofolate reductase (zDHFR) protein with gold nanoparticles and various osmolytes (glycerol, glucose and betain). Present observations revealed that the interaction of gold nanoparticles (AuNPs) with bacteria at the cellular level helps in maintaining the stability of protein more effectively than osmolytes which could be used for many biological and pharmacological approaches although glycerol as an osmolyte also stabilizes the protein at a significant level.

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