Accelerating molecular simulations of proteins using Bayesian inference on weak information

Proceedings of the National Academy of Sciences of the United States of America
Alberto PerezKen A Dill

Abstract

Atomistic molecular dynamics (MD) simulations of protein molecules are too computationally expensive to predict most native structures from amino acid sequences. Here, we integrate "weak" external knowledge into folding simulations to predict protein structures, given their sequence. For example, we instruct the computer "to form a hydrophobic core," "to form good secondary structures," or "to seek a compact state." This kind of information has been too combinatoric, nonspecific, and vague to help guide MD simulations before. Within atomistic replica-exchange molecular dynamics (REMD), we develop a statistical mechanical framework, modeling using limited data with coarse physical insight(s) (MELD + CPI), for harnessing weak information. As a test, we apply MELD + CPI to predict the native structures of 20 small proteins. MELD + CPI samples to within less than 3.2 Å from native for all 20 and correctly chooses the native structures (<4 Å) for 15 of them, including ubiquitin, a millisecond folder. MELD + CPI is up to five orders of magnitude faster than brute-force MD, satisfies detailed balance, and should scale well to larger proteins. MELD + CPI may be useful where physics-based simulations are needed to study protein mechanis...Continue Reading

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Citations

Jan 17, 2016·Current Opinion in Structural Biology·Alberto PerezKen A Dill
Jan 3, 2016·The Journal of Chemical Physics·Alberto PerezKen A Dill
Nov 18, 2015·Journal of Chemical Theory and Computation·Alberto PerezKen A Dill
Nov 4, 2016·The Journal of Physical Chemistry. B·Fernando Bergasa-Caceres, Herschel A Rabitz
Jan 4, 2017·Journal of Chemical Theory and Computation·Joseph A MorroneKen A Dill
Jan 4, 2017·Journal of Chemical Theory and Computation·Joseph A MorroneKen A Dill
Mar 7, 2018·Proceedings of the National Academy of Sciences of the United States of America·Hahnbeom ParkDavid Baker
Nov 17, 2016·Science Advances·Alberto PerezKen A Dill
Mar 27, 2019·Angewandte Chemie·Alberto PerezJustin L MacCallum
Jul 28, 2019·Proteins·James C RobertsonAlberto Perez
May 30, 2019·The Journal of Membrane Biology·Rajeswari AppaduraiAnand Srivastava
Sep 25, 2017·Proteins·Sergey OvchinnikovDavid Baker
Dec 28, 2019·Journal of Computer-aided Molecular Design·Sergei KotelnikovDima Kozakov
Sep 3, 2020·The Journal of Chemical Physics·Emanuel K PeterAlexander Schug
Sep 30, 2017·Wiley Interdisciplinary Reviews. Computational Molecular Science·Alberto PerezKen A Dill
Aug 3, 2019·The Journal of Chemical Physics·Tanmoy SanyalM Scott Shell
Nov 28, 2020·Science·Emiliano BriniKen Dill
Dec 10, 2020·The Journal of Chemical Physics·John W VantAbhishek Singharoy
Jan 7, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Lijun Lang, Alberto Perez
Apr 9, 2021·Methods : a Companion to Methods in Enzymology·Jhullian J AlstonAlex S Holehouse
Jun 19, 2021·Journal of Chemical Information and Modeling·Takaharu MoriYuji Sugita
Jul 17, 2021·The Journal of Physical Chemistry. B·Benjamin LickertGerhard Stock
Aug 7, 2021·Communications Biology·Bhanita Sharma, Ken A Dill
Mar 26, 2019·Journal of Chemical Theory and Computation·Emiliano BriniKen A Dill
May 24, 2019·Journal of Medicinal Chemistry·James W PapatzimasDarren J Derksen
Nov 9, 2018·Journal of Chemical Theory and Computation·James C RobertsonKen A Dill
Jun 17, 2020·Journal of Chemical Theory and Computation·Adrià PérezGianni De Fabritiis
Mar 28, 2018·The Journal of Physical Chemistry. B·Justin L MacCallumKari Gaalswyk
Sep 11, 2020·Journal of Chemical Theory and Computation·Cong LiuKen A Dill
Mar 9, 2018·The Journal of Physical Chemistry. B·Yunhui Ge, Vincent A Voelz
Mar 17, 2018·Journal of Chemical Theory and Computation·Alberto PerezKen Dill
Mar 24, 2020·Journal of Chemical Information and Modeling·Thomas DoddIvaylo Ivanov
Sep 4, 2021·Frontiers in Molecular Biosciences·Kari GaalswykJustin L MacCallum
Nov 9, 2021·The Journal of Physical Chemistry. B·Adam K NijhawanKevin L Kohlstedt
Dec 9, 2021·Journal of Chemical Theory and Computation·Cong LiuKen A Dill

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