Can System Truncation Speed up Ligand-Binding Calculations with Periodic Free-Energy Simulations?

Journal of Chemical Information and Modeling
Francesco ManzoniUlf Ryde

Abstract

We have investigated whether alchemical free-energy perturbation calculations of relative binding energies can be sped up by simulating a truncated protein. Previous studies with spherical nonperiodic systems showed that the number of simulated atoms could be reduced by a factor of 26 without affecting the calculated binding free energies by more than 0.5 kJ/mol on average ( Genheden, S.; Ryde, U. J. Chem. Theory Comput. 2012 , 8 , 1449 ), leading to a 63-fold decrease in the time consumption. However, such simulations are rather slow, owing to the need of a large cutoff radius for the nonbonded interactions. Periodic simulations with the electrostatics treated by Ewald summation are much faster. Therefore, we have investigated if a similar speed-up can be obtained also for periodic simulations. Unfortunately, our results show that it is harder to truncate periodic systems and that the truncation errors are larger for these systems. In particular, residues need to be removed from the calculations, which means that atoms have to be restrained to avoid that they move in an unrealistic manner. The results strongly depend on the strength on this restraint. For the binding of seven ligands to dihydrofolate reductase and ten inhibito...Continue Reading

References

Apr 22, 2003·Nature Structural Biology·Jirundon YuvaniyamaYongyuth Yuthavong
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Dec 11, 2007·The Journal of Chemical Physics·Thomas SteinbrecherDavid A Case
Sep 11, 2008·Journal of Computer-aided Molecular Design·Jacob Kongsted, Ulf Ryde
Dec 3, 2008·The Journal of Chemical Physics·Michael R Shirts, John D Chodera
Mar 26, 2009·Accounts of Chemical Research·William L Jorgensen
Apr 3, 2009·Drug Discovery Today·Scott P BrownPhilip J Hajduk
Jul 2, 2009·Journal of Computational Chemistry·Giulio RastelliMiriam Sgobba
Jul 15, 2009·Journal of Computational Chemistry·Samuel Genheden, Ulf Ryde
May 29, 2010·Journal of Computer-aided Molecular Design·Julien Michel, Jonathan W Essex
Mar 23, 2011·Journal of Chemical Information and Modeling·Samuel GenhedenUlf Ryde
Sep 29, 2011·Journal of Computational Chemistry·Thomas SteinbrecherDavid A Case
Dec 27, 2011·Journal of Computer-aided Molecular Design·Paulius MikulskisUlf Ryde
Dec 27, 2012·The Journal of Chemical Physics·David L Mobley, Pavel V Klimovich
Apr 19, 2013·Physical Chemistry Chemical Physics : PCCP·Frithjof GodschalkUlf Ryde
Aug 29, 2013·Chemical Reviews·G Andrés CisnerosCeleste Sagui
Nov 5, 2013·Journal of Chemical Theory and Computation·Joseph W KausJ Andrew McCammont
Nov 22, 2013·Journal of Chemical Information and Modeling·Clara D Christ, Thomas Fox
Sep 30, 2014·Journal of Chemical Information and Modeling·Paulius MikulskisUlf Ryde
Apr 4, 2015·Expert Opinion on Drug Discovery·Samuel Genheden, Ulf Ryde
Nov 20, 2015·Journal of Chemical Theory and Computation·Edward HarderRichard A Friesner
Jul 8, 2014·Journal of Chemical Theory and Computation·Niels Hansen, Wilfred F van Gunsteren
Apr 10, 2012·Journal of Chemical Theory and Computation·Samuel Genheden, Ulf Ryde
Apr 15, 2016·Chemical Reviews·Ulf Ryde, Pär Söderhjelm

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.