scholarly journals CHARMM-GUI Free Energy Calculator for Absolute and Relative Ligand Solvation and Binding Free Energy Simulations

2020 ◽  
Vol 16 (11) ◽  
pp. 7207-7218 ◽  
Author(s):  
Seonghoon Kim ◽  
Hiraku Oshima ◽  
Han Zhang ◽  
Nathan R. Kern ◽  
Suyong Re ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Energy Simulations

scholarly journals New Tools for Conformational and Binding Free Energy Simulations

2019 ◽  
Vol 116 (3) ◽  
pp. 142a
Author(s):  
Giacomo Fiorin ◽  
Grace Brannigan ◽  
Jérôme Hénin
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Energy Simulations

scholarly journals CHARMM-GUI Free Energy Calculator for Practical Ligand Binding Free Energy Simulations with AMBER

2021 ◽  
Vol 61 (9) ◽  
pp. 4145-4151
Author(s):  
Han Zhang ◽  
Seonghoon Kim ◽  
Timothy J. Giese ◽  
Tai-Sung Lee ◽  
Jumin Lee ◽  
...  
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Binding Free Energy ◽  
Energy Simulations

scholarly journals Molecular Dynamics Free Energy Simulations Reveal the Mechanism for the Antiviral Resistance of the M66I HIV-1 Capsid Mutation

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 920
Author(s):  
Qinfang Sun ◽  
Ronald M. Levy ◽  
Karen A. Kirby ◽  
Zhengqiang Wang ◽  
Stefan G. Sarafianos ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Drug Resistance ◽  
Free Energy ◽  
Energy Cost ◽  
Binding Free Energy ◽  
Resistance Mutation ◽  
Side Chain ◽  
Ligand Interaction ◽  
Energy Simulations ◽  
Hiv 1

While drug resistance mutations can often be attributed to the loss of direct or solvent-mediated protein−ligand interactions in the drug-mutant complex, in this study we show that a resistance mutation for the picomolar HIV-1 capsid (CA)-targeting antiviral (GS-6207) is mainly due to the free energy cost of the drug-induced protein side chain reorganization in the mutant protein. Among several mutations, M66I causes the most suppression of the GS-6207 antiviral activity (up to ~84,000-fold), and only 83- and 68-fold reductions for PF74 and ZW-1261, respectively. To understand the molecular basis of this drug resistance, we conducted molecular dynamics free energy simulations to study the structures, energetics, and conformational free energy landscapes involved in the inhibitors binding at the interface of two CA monomers. To minimize the protein−ligand steric clash, the I66 side chain in the M66I−GS-6207 complex switches to a higher free energy conformation from the one adopted in the apo M66I. In contrast, the binding of GS-6207 to the wild-type CA does not lead to any significant M66 conformational change. Based on an analysis that decomposes the absolute binding free energy into contributions from two receptor conformational states, it appears that it is the free energy cost of side chain reorganization rather than the reduced protein−ligand interaction that is largely responsible for the drug resistance against GS-6207.

Calculation of free energy changes due to mutations from alchemical free energy simulations

2015 ◽  
Vol 14 (03) ◽  
pp. 1550023 ◽  
Author(s):  
M. Harunur Rashid ◽  
Germano Heinzelmann ◽  
Serdar Kuyucak
Keyword(s):  
Free Energy ◽  
Fundamental Problem ◽  
Binding Free Energy ◽  
Computational Design ◽  
Md Simulations ◽  
Binding Mode ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
Energy Simulations ◽  
Alchemical Free Energy

How a mutation affects the binding free energy of a ligand is a fundamental problem in molecular biology/biochemistry with many applications in pharmacology and biotechnology, e.g. design of drugs and enzymes. Free energy change due to a mutation can be determined most accurately by performing alchemical free energy calculations in molecular dynamics (MD) simulations. Here we discuss the necessary conditions for success of free energy calculations using toxin peptides that bind to ion channels as examples. We show that preservation of the binding mode is an essential requirement but this condition is not always satisfied, especially when the mutation involves a charged residue. Otherwise problems with accuracy of results encountered in mutation of charged residues can be overcome by performing the mutation on the ligand in the binding site and bulk simultaneously and in the same system. The proposed method will be useful in improving the affinity and selectivity profiles of drug leads and enzymes via computational design and protein engineering.

scholarly journals Exploring the effectiveness of SARS-CoV-2 3CLpro inhibitors through molecular dynamics and binding free energy simulations

2020 ◽  
Author(s):  
ANDREY PINHEIRO ◽  
GABRIEL XAVIER ◽  
ANDREI SIQUEIRA ◽  
ALEX LIMA ◽  
DÉLIA AGUIAR ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Vaccine Development ◽  
Virus Disease ◽  
Binding Free Energy ◽  
Zinc Database ◽  
Energy Simulations ◽  
Novel Coronavirus ◽  
Dynamics Simulations ◽  
The Impact

Abstract In December 2019, in the city of Wuhan in China, a novel Coronavirus was identified as the causative agent of a Severe Acute Respiratory Syndrome, later called Corona Virus Disease 2019 (COVID-19). Since the identification of the agent and sequencing of its genome, proteases such as 3CLpro and PLprothat participate in the viral cycle have been identified as possible pharmacological targets. This study aimed to evaluate the affinity of SARS-CoV-2 3CLpro (PDB 6LU7) concerning promising binders identified by other studies using virtual screening against the ZINC database and other molecules within the possibility of inhibiting the protease, such as Hydroxychloroquine, Chloroquine, and Remdesivir. Around 1,140 ns of molecular dynamics simulations were performed to evaluate stability and binding free energy values of protein-ligand complexes (60 ns for each ligand). The estimated affinity, based on 5000 frames trajectories, revealed that N3, 11b, remdesivir and a ZINC database ligand are the most promising inhibitors of 3CLpro.Given that most studies present energy results based on docking runs and one-frame coordinates analyses, the results found may present a more accurate energy value and may help experimental approaches to developing a drug against COVID-19. Despite the importance of vaccine development, alternative strategies, such as specific viral inhibitors, are important to reduce the impact of the disease on people.

Large-Scale Assessment of Binding Free Energy Calculations in Active Drug Discovery Projects

2020 ◽  
Author(s):  
Christina Schindler ◽  
Hannah Baumann ◽  
Andreas Blum ◽  
Dietrich Böse ◽  
Hans-Peter Buchstaller ◽  
...  
Keyword(s):  
Free Energy ◽  
Drug Discovery ◽  
Large Scale ◽  
Active Drug ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Energy Calculation ◽  
Large Scale Assessment ◽  
New Public ◽  
Binding Free Energy Calculations

Here we present an evaluation of the binding affinity prediction accuracy of the free energy calculation method FEP+ on internal active drug discovery projects and on a large new public benchmark set.<br>

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