Free energy simulations for protein ligand binding and stability

Hage, Krystel El; Mondal, Padmabati; Meuwly, Markus

doi:10.1080/08927022.2017.1416115

Cited by 17 publications

(16 citation statements)

References 176 publications

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“…The RMSD computes the direct changes in the atoms of superimposed proteins and an acceptable approach to assess the stability of protein/ligand complexes [ [90] , [91] , [92] , [93] ]. The RMSD values of the Cα-backbone atoms of SARS-CoV-2 PL pro in complex to the three PL pro potential inhibitors were calculated with respect to the initial structure and compared with apo-protein in an unbound form.…”

Section: Resultsmentioning

confidence: 99%

“…The RMSF measures the local protein flexibility and proved to be an excellent parameter to investigate the protein's residual flexibility over the simulation period [ 90 , 92 ]. The time average of protein backbone RMSF values of the 315 amino acids of SARS-CoV-2 PL pro protein with and without the three candidate compounds was calculated over the 50 ns simulation period.…”

Section: Resultsmentioning

confidence: 99%

“…Hydrogen bonds play a crucial role as stabilizing forces for a ligand-protein complex [ [90] , [91] , [92] ]. The total number of hydrogen bonds formed between the three candidate compounds and SARS-CoV-2 PL pro is showing in Fig.…”

Section: Resultsmentioning

confidence: 99%

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Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches

Alamri

Qamar

Mirza

et al. 2020

Journal of Pharmaceutical Analysis

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The papain-like protease (PL pro ) is vital for the replication of coronaviruses (CoVs), as well as for escaping innate-immune responses of the host. Hence, it has emerged as an attractive antiviral drug-target. In this study, computational approaches were employed, mainly the structure-based virtual screening coupled with all-atom molecular dynamics (MD) simulations to computationally identify specific inhibitors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PL pro , that can be further developed as potential pan-PL pro based broad-spectrum antiviral drugs. The sequence, structure, and functional conserveness of most deadly human CoVs PL pro were exploited, and it was revealed that functionally important catalytic triad residues are well conserved among SARS-CoV, SARS-CoV-2, and middle east respiratory syndrome coronavirus (MERS-CoV). The subsequent screening of a focused protease inhibitors database composed of ∼7000 compounds resulted in the identification of three candidate compounds, ADM_13083841, LMG_15521745, and SYN_15517940. These three compounds established conserved interactions which were further explored through MD simulations, free energy calculations, and residual energy contribution estimated by MM-PB(GB)SA method. All these compounds showed stable conformation and interacted well with the active residues of SARS-CoV-2 PL pro and showed consistent interaction profile with SARS-CoV PL pro and MERS-CoV PL pro as well. Conclusively, the reported SARS-CoV-2 PL pro specific compounds could serve as seeds for developing potent pan-PL pro based broad-spectrum antiviral drugs against deadly human coronaviruses. Moreover, the presented information related to binding site residual energy contribution could lead to further optimization of these compounds.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches

Alamri

Qamar

Mirza

et al. 2020

Journal of Pharmaceutical Analysis

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“…Umbrella sampling method and the WHAM algorithm are commonly used to obtain energy landscape for ligand‐protein binding energy and to generate free energy profiles for the conformational transition of protein molecules . Current findings suggest that it can also be used for studying polymer adsorption.…”

Section: Resultsmentioning

confidence: 99%

Molecular Dynamics Simulation of Ethylene/Hexene Copolymer Adsorption onto Graphene: New Insight into Thermal Gradient Interaction Chromatography

Brunel

Boyron

Boisson

2019

Macro Chemistry & Physics

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Crystallization‐based fractionation techniques are powerful methods for the analysis of short‐chain branching (SCB) in linear low‐density polyethylene. Recently, thermal gradient interaction chromatography (TGIC) has been developed for SCB determination of semi‐crystalline and amorphous polyolefins. In TGIC, the fractionation mechanism relies on the interaction of polyolefin chains with a graphite surface upon temperature change for a given solvent strength. Using molecular dynamics simulations, both the enthalpic and entropic contributions responsible for the separation of short‐chain branched polyethylene are estimated. A new thermodynamic framework for understanding the fractionation mechanism of TGIC is proposed. It is confirmed that at high SCB content, the decrease of the adsorption enthalpy is mostly due to the increased steric hindrance of short branches. However, for low chain branching density, strong increase of the persistence length observed during adsorption decreases the conformational entropy of the polymer and thus counter‐balances the favorable adsorption enthalpy. This entropic contribution may also explain the narrowing of the peak observed experimentally with low short‐chain branching density at high elution temperature.

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“…The results show that convergence within an US window is obtained after ≈ 1 ns of accumulation time after which the free energy contribution for the particular window fluctuates around its average. 75…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

From in silica to in silico: retention thermodynamics at solid–liquid interfaces

Hage

Bemish

Meuwly

2018

Phys. Chem. Chem. Phys.

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The dynamics of solvated molecules at the solid/liquid interface is essential for a molecular-level understanding for the solution thermodynamics in reversed phase liquid chromatography (RPLC). The heterogeneous nature of the systems and the competing intermolecular interactions makes solute retention in RPLC a surprisingly challenging problem which benefits greatly from modelling at atomistic resolution. However, the quality of the underlying computational model needs to be sufficiently accurate to provide a realistic description of the energetics and dynamics of systems, especially for solution-phase simulations. Here, the retention thermodynamics and the retention mechanism of a range of benzene-derivatives in C18 stationary-phase chains in contact with water/methanol mixtures is studied using point charge (PC) and multipole (MTP) electrostatic models. The results demonstrate that free energy simulations with a faithful MTP representation of the computational model provide quantitative and molecular level insight into the thermodynamics of adsorption/desorption in chromatographic systems while a conventional PC representation fails in doing so. This provides a rational basis to develop more quantitative and validated models for the optimization of separation systems.

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Free energy simulations for protein ligand binding and stability

Cited by 17 publications

References 176 publications

Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches

Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches

Molecular Dynamics Simulation of Ethylene/Hexene Copolymer Adsorption onto Graphene: New Insight into Thermal Gradient Interaction Chromatography

From in silica to in silico: retention thermodynamics at solid–liquid interfaces

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