Monte Carlo simulations of proteins at constant pH with generalized Born solvent, flexible sidechains, and an effective dielectric boundary

Journal of Computational Chemistry
Savvas Polydorides, Thomas Simonson

Abstract

Titratable residues determine the acid/base behavior of proteins, strongly influencing their function; in addition, proton binding is a valuable reporter on electrostatic interactions. We describe a method for pK(a) calculations, using constant-pH Monte Carlo (MC) simulations to explore the space of sidechain conformations and protonation states, with an efficient and accurate generalized Born model (GB) for the solvent effects. To overcome the many-body dependency of the GB model, we use a "Native Environment" approximation, whose accuracy is shown to be good. It allows the precalculation and storage of interactions between all sidechain pairs, a strategy borrowed from computational protein design, which makes the MC simulations themselves very fast. The method is tested for 12 proteins and 167 titratable sidechains. It gives an rms error of 1.1 pH units, similar to the trivial "Null" model. The only adjustable parameter is the protein dielectric constant. The best accuracy is achieved for values between 4 and 8, a range that is physically plausible for a protein interior. For sidechains with large pKa shifts, ≥2, the rms error is 1.6, compared to 2.5 with the Null model and 1.5 with the empirical PROPKA method.

References

Jan 1, 1977·Annual Review of Biophysics and Bioengineering·F M Richards
Jun 1, 1991·Journal of Biomolecular Structure & Dynamics·P TufferyR Lavery
Mar 1, 1980·Journal of Biochemistry·S KuramitsuK Nakashima
Feb 14, 1995·Proceedings of the National Academy of Sciences of the United States of America·Thomas Simonson, D Perahia
May 6, 1994·Journal of Molecular Biology·J AntosiewiczM K Gilson
Jun 21, 1996·Journal of Molecular Biology·T KesvateraS Linse
Oct 6, 1997·Science·B I Dahiyat, Stephen L Mayo
Jun 6, 1998·Advances in Protein Chemistry·M SchaeferM Karplus
Aug 26, 1998·Folding & Design·A G Street, Stephen L Mayo
Aug 19, 1999·Proteins·T KesvateraS Linse
Sep 2, 2000·Biophysical Journal·Y H KaoBertrand García-Moreno E
Apr 12, 2001·Biochemistry·Alexey V OnufrievG Matthias Ullmann
Dec 12, 2001·Current Opinion in Chemical Biology·D L Zechel, S G Withers
Jun 25, 2002·Journal of Molecular Biology·Raphael GueroisLuis Serrano
Sep 6, 2002·Journal of Computational Chemistry·Alexey V OnufrievDonald Bashford
Nov 25, 2003·Advances in Protein Chemistry·Jay W Ponder, David A Case
Dec 4, 2003·Acta Crystallographica. Section D, Biological Crystallography·Luc MoulinierThomas Simonson
Apr 1, 2004·Journal of the American Chemical Society·Thomas SimonsonDavid A Case
Apr 20, 2004·Current Opinion in Structural Biology·Michael Feig, Charles L Brooks
Jul 29, 2004·Proteins·Michael S LeeCharles L Brooks
Oct 14, 2004·Journal of Computational Chemistry·John MonganJ Andrew McCammon
Apr 28, 2005·Journal of Molecular Biology·Jinrang KimM R Gunner
Mar 10, 2006·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·David Baker
May 13, 2006·Annual Review of Biophysics and Biomolecular Structure·Glenn L Butterfoss, Brian Kuhlman
Jul 11, 2006·Protein Science : a Publication of the Protein Society·Eric S ZollarsStephen L Mayo
Jul 21, 2006·The Journal of Physical Chemistry. B·Georgios Archontis, Thomas Simonson
Aug 2, 2006·Biochemistry·Jana Khandogin, Charles L Brooks
Mar 16, 2007·Proceedings of the National Academy of Sciences of the United States of America·P BarthP B Harbury
Dec 7, 2007·Proteins·Gernot Kieseritzky, Ernst-Walter Knapp
Dec 12, 2007·Journal of Computational Chemistry·Marcel Schmidt am BuschThomas Simonson
Jan 25, 2008·Proteins·Miguel Machuqueiro, António M Baptista
Feb 29, 2008·Current Opinion in Structural Biology·Jianhan ChenJana Khandogin
Jan 24, 2009·The Journal of Biological Chemistry·C Nick PaceJ Martin Scholtz
May 16, 2009·Journal of Computational Chemistry·B R BrooksM Karplus
Jun 18, 2009·Proteins·Carlos A CastañedaBertrand E García-Moreno
Aug 13, 2010·The Journal of Physical Chemistry. B·Alexey AleksandrovThomas Simonson
Jan 1, 2009·Methods in Enzymology·Jason A Wallace, Jana K Shen
Jul 8, 2011·Journal of Computational Chemistry·Jennifer L Knight, Charles L Brooks
Oct 18, 2011·Proteins·Emil AlexovJ Michael Word
Sep 6, 2012·Biophysical Journal·Krishna Praneeth Kilambi, Jeffrey J Gray
Sep 17, 2013·Journal of Computational Chemistry·Thomas SimonsonGeorgios Archontis
Apr 9, 2013·Journal of Chemical Theory and Computation·Hai NguyenCarlos Simmerling
Jul 10, 2012·Journal of Chemical Theory and Computation·Boris Aguilar, Alexey V Onufriev
Feb 8, 2011·Journal of Chemical Theory and Computation·Mats H M OlssonJan H Jensen
May 1, 2005·Journal of Chemical Theory and Computation·Jessica M J SwansonJ Andrew McCammon

Citations

Oct 28, 2015·Journal of Computational Chemistry·Karen DruartThomas Simonson
May 24, 2014·Journal of Computational Chemistry·Thomas Gaillard, Thomas Simonson
Mar 8, 2016·Proteins·Thomas GaillardThomas Simonson
Oct 25, 2016·Journal of Chemical Theory and Computation·Karen DruartThomas Simonson
Apr 11, 2017·Journal of Chemical Theory and Computation·David MignonThomas Simonson
Jul 28, 2017·Journal of Computational Chemistry·Francesco VillaThomas Simonson
Jan 20, 2018·Physical Review. E·Christopher W WahleGeorge M Thurston
Aug 24, 2018·The Journal of Chemical Physics·Francesco VillaThomas Simonson
Jan 10, 2020·PLoS Computational Biology·Vaitea OpuuThomas Simonson
Aug 11, 2020·The Journal of Chemical Physics·Eleni MichaelGeorgios Archontis

Related Concepts

In Silico
Hydrogen-Ion Concentration
Monte Carlo Method
Protein Conformation
Solvents
Anatomical Space Structure
Simulation
Proton Transport
Computed (Procedure)
Proton Binding

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.

Synthetic Genetic Array Analysis

Synthetic genetic arrays allow the systematic examination of genetic interactions. Here is the latest research focusing on synthetic genetic arrays and their analyses.

Neural Activity: Imaging

Imaging of neural activity in vivo has developed rapidly recently with the advancement of fluorescence microscopy, including new applications using miniaturized microscopes (miniscopes). This feed follows the progress in this growing field.

Computational Methods for Protein Structures

Computational methods employing machine learning algorithms are powerful tools that can be used to predict the effect of mutations on protein structure. This is important in neurodegenerative disorders, where some mutations can cause the formation of toxic protein aggregations. This feed follows the latests insights into the relationships between mutation and protein structure leading to better understanding of disease.

Congenital Hyperinsulinism

Congenital hyperinsulinism is caused by genetic mutations resulting in excess insulin secretion from beta cells of the pancreas. Here is the latest research.

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.

Epigenetic Memory

Epigenetic memory refers to the heritable genetic changes that are not explained by the DNA sequence. Find the latest research on epigenetic memory here.

Cell Atlas of the Human Eye

Constructing a cell atlas of the human eye will require transcriptomic and histologic analysis over the lifespan. This understanding will aid in the study of development and disease. Find the latest research pertaining to the Cell Atlas of the Human Eye here.

Femoral Neoplasms

Femoral Neoplasms are bone tumors that arise in the femur. Discover the latest research on femoral neoplasms here.