-
The pH value represents the acidity of the solution and plays a key role in many life events linked to human diseases. For instance, the β-site amyloid precursor protein cleavage enzyme, BACE1, which is a major therapeutic target of treating Alzheimer’s disease, functions within a narrow pH region around 4.5. In addition, the sodium-proton antiporter NhaA from Escherichia coli is activated only when the cytoplasmic pH is higher than 6.5 and the activity reaches a maximum value around pH 8.8. To explore the molecular mechanism of a protein regulated by pH, it is important to measure, typically by nuclear magnetic resonance, the binding affinities of protons to ionizable key residues, namely
$ {\mathrm{p}}{K}_{{\mathrm{a}}} $ values, which determine the deprotonation equilibria under a pH condition. However, wet-lab experiments are often expensive and time consuming. In some cases, owing to the structural complexity of a protein,$ {\mathrm{p}}{K}_{{\mathrm{a}}} $ measurements become difficult, making theoretical$ {\mathrm{p}}{K}_{{\mathrm{a}}} $ predictions in a dry laboratory more advantageous. In the past thirty years, many efforts have been made to accurately and fast predict protein$ {\mathrm{p}}{K}_{{\mathrm{a}}} $ with physics-based methods. Theoretically, constant pH molecular dynamics (CpHMD) method that takes conformational fluctuations into account gives the most accurate predictions, especially the explicit-solvent CpHMD model proposed by Huang and coworkers (2016 J. Chem. Theory Comput. 12 5411 ) which in principle is applicable to any system that can be described by a force field. However, lengthy molecular simulations are usually necessary for the extensive sampling of conformation. In particular, the computational complexity increases significantly if water molecules are included explicitly in the simulation system. Thus, CpHMD is not suitable for high-throughout computing requested in industry circle. To accelerate$ {\mathrm{p}}{K}_{{\mathrm{a}}} $ prediction, Poisson-Boltzmann (PB) or empirical equation-based schemes, such as H++ and PropKa, have been developed and widely used where$ {\mathrm{p}}{K}_{{\mathrm{a}}} $ values are obtained via one-structure calculations. Recently, artificial intelligence (AI) is applied to the area of protein$ {\mathrm{p}}{K}_{{\mathrm{a}}} $ prediction, which leads to the development of DeepKa by Huang laboratory (2021 ACS Omega 6 34823 ), the first AI-driven$ {\mathrm{p}}{K}_{{\mathrm{a}}} $ predictor. In this paper, we review the advances in protein$ {\mathrm{p}}{K}_{{\mathrm{a}}} $ prediction contributed mainly by CpHMD methods, PB or empirical equation-based schemes, and AI models. Notably, the modeling hypotheses explained in the review would shed light on future development of more powerful protein$ {\mathrm{p}}{K}_{{\mathrm{a}}} $ predictors.-
Keywords:
- molecular dynamics /
- Poisson-Boltzmann equation /
- machine learning /
- $ {\mathrm{p}}{K}_{{\mathrm{a}}} $ prediction
[1] Casey J R, Grinstein S, Orlowski J 2010 Nat. Rev. Mol. Cell Biol. 11 50
Google Scholar
[2] Qian H, Wu X L, Du X M, Yao X, Zhao X, Lee J, Yang H Y, Yan N 2020 Cell 182 98
Google Scholar
[3] Yang G H, Zhou R, Zhou Q, Guo X F, Yan C Y, Ke M, Lei J L, Shi Y G 2019 Nature 565 192
Google Scholar
[4] Chung H S, Piana-Agostinetti S, Shaw D E, Eaton W A 2015 Science 349 1504
Google Scholar
[5] Nasica-Labouze J, Nguyen P H, Sterpone F, Berthoumieu O, Buchete N, Cote S, Simone A D, Doig A J, Faller P, Garcia A, Laio A, Li M S, Melchionna S, Mousseau N, Mu Y, Paravastu A, Pasquali S, Rosenman D J, Strodel B, Tarus B, Viles J H, Zhang T, Wang C, Derreumaux P 2015 Chem. Rev. 115 3518
Google Scholar
[6] Morrow B H, Payne G F, Shen J 2015 J. Am. Chem. Soc. 137 13024
Google Scholar
[7] Kumar A, Hossain R A, Yost S A, Bu W, Wang Y, Dearborn A D, Grakoui A, Cohen J I, Marcotrigiano J 2021 Nature 598 521
Google Scholar
[8] Singharoy A, Maffeo C, Delgado-Magnero K H, Swainsbury D J K, Sener M, Kleinekathofer U, Vant J W, Nguyen J, Hitchcock A, Isralewitz B, Teo I, Chandler D E, Stone J E, Phillips J C, Pogorelov T V, Mallus M I, Chipot C, Luthey-Schulten Z, Tieleman D P, Hunter C N, Schulten K 2019 Cell 179 1098
Google Scholar
[9] Shimizu H, Tosaki A, Kaneko K, Hisano T, Sakurai T, Nukina N 2008 Mol. Cell Biol. 28 3663
Google Scholar
[10] Ellis C R, Shen J 2015 J. Am. Chem. Soc. 137 9543
Google Scholar
[11] Thurlkill R L, Grimsley G R, Scholtz J M, Pace C N 2006 Protein Sci. 15 1214
Google Scholar
[12] Jensen J H, Li H, Robertson A D, Molina P A 2005 J. Phys. Chem. A 109 6634
Google Scholar
[13] Baptista A M, Martel P J, Petersen S B 1997 Proteins 27 523
Google Scholar
[14] Shi C, Wallace J A, Shen J K 2012 Biophys. J. 102 1590
Google Scholar
[15] Qing R, Hao S L, Smorodina E, Jin D, Zalevsky A, Zhang S G 2022 Chem. Rev. 122 14085
Google Scholar
[16] Henderson J A, Liu R, Harris J A, Huang Y D, de Oliveria V M, Shen J D 2022 Liv. J. Comput. Mol. 4 1563
Google Scholar
[17] Georgescu R E, Alexov E G, Gunner M R 2002 Biophys. J. 83 1731
Google Scholar
[18] Anandakrishnan R, Aguilar B, Onufriev A V 2012 Nucleic Acids Res. 40 W537
Google Scholar
[19] Dolinsky T J, Nielsen J E, McCammon J A, Baker N A 2004 Nucleic Acids Res. 32 665
Google Scholar
[20] Wang L, Li L, Alexov E 2015 Proteins. 83 2186
Google Scholar
[21] Reis Pedro B P S, Vila-Viçosa D, Rocchia W, Machuqueiro M 2020 J. Chem. Inf. Model. 60 4442
Google Scholar
[22] Huang Y D, Yue Z, Tsai C C, Henderson J A, Shen J 2018 J. Phys. Chem. Lett. 9 1179
Google Scholar
[23] Li H, Robertson A D, Jensen J H 2005 Proteins 61 704
Google Scholar
[24] Olsson Mats H M, Søndergaard C R, Rostkowski M, Jensen J H 2011 J. Chem. Theory Comput. 7 525
Google Scholar
[25] Cai Z T, Luo F F, Wang Y X, Li E L, Huang Y D 2021 ACS Omega 6 34823
Google Scholar
[26] Gokcan H, Lsayev O 2022 Chem. Sci. 13 2462
Google Scholar
[27] Chen A Y, Lee J, Damjanovic Ana, Brooks B R 2022 J. Chem. Theory Comput. 184 2673
Google Scholar
[28] Reis Pedro B P S, Bertolini M, Montanari F, Rocchia W, Machuqueiro M, Clevert D A 2022 J. Chem. Theory Comput. 18 5068
Google Scholar
[29] Cai Z T, Liu T Z, Lin Q L, He J H, Lei X W, Luo F F, Huang Y D 2023 J. Chem. Inf. Model 63 2936
Google Scholar
[30] Baptista A M, Teixeira V H, Soares C M 2002 J. Chem. Phys. 117 4184
Google Scholar
[31] Lee M S, Salsbury F R, Brooks Ⅲ C L 2004 Proteins 56 738
Google Scholar
[32] Mongan J, Case D A, McCammon J A 2004 J. Comput. Chem. 25 2038
Google Scholar
[33] Meng Y, Roitberg A E 2010 J. Chem. Theory Comput. 6 1401
Google Scholar
[34] Swails J M, York D M, Roitberg A E 2014 J. Chem. Theory Comput. 10 1341
Google Scholar
[35] Machuqueiro M, Baptista A M 2006 J. Phys. Chem. B 110 2927
Google Scholar
[36] Sequeira J G N, Rodrigues F E P, Silva T G D, Reis Pedro B P S, Machuqueiro M 2022 J. Phys. Chem. B. 126 7870
Google Scholar
[37] Huang Y D, Chen W, Dotson D L, Beckstein O, Shen J 2016 Nat. Commun. 7 12940
Google Scholar
[38] Stern H A 2007 J. Chem. Phys. 126 164112
Google Scholar
[39] Essmann U, Perera L, Berkowitz M L, Darden T, Lee H, Pedersen L G 1995 J. Chem. Phys. 103 8577
Google Scholar
[40] Chen Y, Roux B 2015 J. Chem. Theory Comput. 11 3919
Google Scholar
[41] Radak B K, Chipot C, Suh D, Jo S, Jiang W, Philips J C, Schulten K, Roux B 2017 J. Chem. Theory Comput. 13 5933
Google Scholar
[42] Wang R X, Fang X L, Lu Y P, Yang C Y, Wang S M 2005 J. Med. Chem. 48 4111
Google Scholar
[43] Pieri E, Ledentu V, Sahlin M, Dehez F, Olivucci M, Ferre N 2019 J. Chem. Theory Comput. 15 4535
Google Scholar
[44] de Oliveria V M, Liu R, Shen J 2022 Curr. Opin. Struct. Biol. 77 102498
Google Scholar
[45] Kong X, Brooks III C L 1996 J. Chem. Phys. 105 2414
Google Scholar
[46] Khandogin J, Brooks Ⅲ C L 2005 Biophys. J. 89 141
Google Scholar
[47] Nguyen H, Maier J, Huang H, Perrone V, Simmerling C 2014 J. Am. Chem. Soc. 136 13959
Google Scholar
[48] Huang Y D, Harris R C, Shen J 2018 J. Chem. Inf. Model. 58 1372
Google Scholar
[49] Liu R, Yue Z, Tsai C C, Shen J 2019 J. Am. Chem. Soc. 141 6553
Google Scholar
[50] Harris R C, Liu R, Shen, J 2020 J. Chem. Theory Comput. 16 3689
Google Scholar
[51] Liu R, Zhan S, Che Y, Shen J 2022 J. Med. Chem. 65 1525
Google Scholar
[52] Yao X, Chen C, Wang Y, Dong S, Liu Y, Li Y, Cui Z, Gong W, Perrett S, Yao L, Lamed R, Bayer E A, Cui Q, Feng Y 2020 Sci. Adv. 6 eabd7182
Google Scholar
[53] Verma N, Henderson J A, Shen J 2020 J. Am. Chem Soc. 142 21883
Google Scholar
[54] Arthur E J, Brooks III C L 2016 J. Comput. Chem. 37 2171
Google Scholar
[55] Harris R C, Shen J 2019 J. Chem. Inf. Model. 59 4821
Google Scholar
[56] Wallace J A, Shen J K 2011 J. Chem. Theory Comput. 7 2617
Google Scholar
[57] Henderson J A, Huang Y D, Beckstein O, Shen J 2020 Proc. Natl. Acad. Sci. U. S. A. 117 25517
Google Scholar
[58] Chen W, Huang Y D, Shen J 2016 J. Phys. Chem. Lett. 7 3961
Google Scholar
[59] Yue Z, Li C, Voth G A, Swanson J M J 2019 J. Am. Chem. Soc. 141 13421
Google Scholar
[60] Vo Q N, Mahinthichaichan P, Shen J, Ellis C R 2021 Nat. Commun. 12 984
Google Scholar
[61] Li Z, Zhang X, Wang Q, Li C, Zhang N, Zhang X, Xu B, Ma B, Schrader T E, Coates L, Kovalevsky A, Huang Y D, Wan Q 2018 ACS Catal. 8 8058
Google Scholar
[62] Tsai C C, Yue Z, Shen J 2019 J. Am. Chem. Soc. 141 15092
Google Scholar
[63] Goh G B, Knight J L, Brooks III C L 2012 J. Chem. Theory Comput. 8 36
Google Scholar
[64] Wallace J A, Shen J K 2012 J. Chem. Phys. 137 184105
Google Scholar
[65] Chen W, Shen J K 2014 J. Comput. Chem. 35 1986
Google Scholar
[66] Huang Y D, Chen W, Wallace J A, Shen J 2016 J. Chem. Theory Comput. 12 5411
Google Scholar
[67] Harris J A, Liu R, de Oliveira V M, Vázquez-Montelongo E A, Henderson J A, Shen J 2022 J. Chem. Theory Comput. 18 7510
Google Scholar
[68] Chen W, Wallace J A, Yue Z, Shen J K 2013 Biophys. J. 105 L15
Google Scholar
[69] Wallace J A, Shen J K 2009 Methods Enzymol. 466 455
Google Scholar
[70] Ullmann G M 2003 J. Phys. Chem. B 107 1263
Google Scholar
[71] Goh G B, Hulbert B S, Zhou H, Brooks Ⅲ C L 2014 Proteins 82 1319
Google Scholar
[72] Webb H, Tynan-Connolly B M, Lee G M, Farrell D, O’Meara F, Sondergaard C R, Teilum K, Hewage C, Mclntosh L P, Nielsen J E 2010 Proteins 79 685-702
Google Scholar
[73] Rocklin G J, Mobley D L, Dill K A, Hunenberger P H 2013 J. Chem. Phys. 139 184103
Google Scholar
[74] Bignucolo O, Chipot C, Kellenberger S, Roux B 2022 J. Phys. Chem. B. 126 6868
Google Scholar
[75] Donnini S, Tegeler F, Groenhof G, Grubmüller H 2011 J. Chem. Theory Comput. 7 1962
Google Scholar
[76] Aho N, Buslaev P, Jansen A, Bauer P, Groenhof G, Hess B 2022 J. Chem. Theory Comput. 18 6148
Google Scholar
[77] Buslaev P, Aho N, Jansen A, Bauer P, Hess B, Groenhof G 2022 J. Chem. Theory Comput. 18 6134
Google Scholar
[78] Knight J L, Brooks Ⅲ C L 2011 J. Comput. Chem. 32 3423
Google Scholar
[79] Donnini S, Ullmann R T, Groenhof G, Grubmüller H 2016 J. Chem. Theory Comput. 12 1040
Google Scholar
[80] Huang Y D, Shuai J 2013 J. Phys. Chem. B 117 6138
Google Scholar
[81] Lemkul J A, Huang J, Roux B, MacKerell A D 2016 Chem. Rev. 116 4983
Google Scholar
[82] Khandogin J, Brooks Ⅲ C L 2006 Biochemistry 45 9363
Google Scholar
[83] Itoh S G, Damjanović A, Brooks B R 2011 Proteins 79 3420
Google Scholar
[84] Dashti D S, Meng Y, Roitberg A E 2012 J. Phys. Chem. B. 116 8805
Google Scholar
[85] Swails J M, Roitberg A E 2012 J. Chem. Theory Comput. 8 4393
Google Scholar
[86] Lee J, Miller B T, Damjanovic A, Brooks B R 2015 J. Chem. Theory Comput. 11 2560
Google Scholar
[87] Lee J, Miller B T, Damjanovic A, Brooks B R 2014 J. Chem. Theory Comput. 10 2738
Google Scholar
[88] Henderson J A, Verma N, Harris R, Shen J 2020 J. Chem. Phys. 153 115101
Google Scholar
[89] Kmiecik S, Gront D, Kolinski M, Wieteska L, Dawid A E, Kolinski A 2016 Chem. Rev. 116 7898
Google Scholar
[90] Bennett W D, Chen A W, Donnini S, Groenhof G, Tieleman D P 2013 Can. J. Chem. 91 839
Google Scholar
[91] da Silva F L B, Sterpone F, Derreumaux P 2019 J. Chem. Theory Comput. 15 3875
Google Scholar
[92] Crünewald F, Souza P C T, Abdizadeh H, Barnoud J, de Vries A H, Marrink S J 2020 J. Chem. Phys. 153 024118
Google Scholar
[93] Reilley D J, Wang J, Dokholyan N V, Alexandrova A N 2021 J. Chem. Theory Comput. 17 4583
Google Scholar
[94] Song Y, Mao J, Gunner M R 2009 J. Comput. Chem. 30 2231
Google Scholar
[95] Wang L, Zhang M, Alexov E 2016 Bioinformatics 32 614
Google Scholar
[96] Pahari S, Sun L, Basu S, Alexov E 2018 Proteins 86 1277
Google Scholar
[97] Bas D C, Rogers D M, Jensen J H 2008 Proteins 73 765
Google Scholar
[98] Sun Z, Wang X, Song J 2017 J. Chem Inf. Model. 57 1621
Google Scholar
[99] Stepniewska-Dziubinska M M, Zielenkiewicz P, Siedlecki P 2018 Bioinformatics 34 3666
Google Scholar
[100] Pahari S, Sun L, Alexov E 2019 Database 2019 baz024
Google Scholar
[101] Ancona N, Bastola A, Alexov E 2023 J. Comput. Biophys. Chem. 22 515
Google Scholar
[102] Reis Pedro B P S, Clevert D A, Machuqueiro M 2022 Bioinformatics 38 297
[103] Wei W, Hogues H, Sulea T 2023 J. Chem. Inf. Model. 63 5169
Google Scholar
[104] Coskun D, Chen W, Clark A J, Lu C, Hardr E D, Wang L, Friesner R A, Miller E B 2022 J. Chem. Theory Comput. 18 7193
Google Scholar
[105] Hagg A, Kirschner K N 2023 J. Chem. Inf. Model. 63 4505
Google Scholar
[106] Bueschbell B, Caniceiro A B, Suzano P M S, Machuqueiro M, Rosário-Ferreira N, Moreira I S 2022 Drug Resist. Updat. 60 100811
Google Scholar
-
图 1 BACE1催化中心质子化态和功能的关系 (a) BACE1三维结构及其催化中心酸性二分体D32和D228; (b) D32和D228质子化态和蛋白质活性随pH的变化规律(D是Asp的缩写)
Figure 1. Relationship between protonation state of BACE1 catalytic center and the function: (a) Crystal structure of BACE1 and the acidic dyad in the catalytic center; (b) protonation states of D32 and D228 and the activity as a function of pH (D is the abbreviation of Asp).
图 2 CpHMD模拟框架
Figure 2. Framework of a CpHMD simulation.
图 3 互变异构滴定模型的3个质子化态以及状态间的转化 (a)天冬氨酸Asp; (b)组氨酸His
Figure 3. Three protonation states and their interconversion in the tautomeric titration model: (a) Aspartic acid; (b) histidine.
图 4 基于C-CpHMD的$ {\mathrm{p}}{K}_{{\mathrm{a}}} $计算 (a)滴定坐标λ和去质子化概率S的轨迹; (b)采用Hill函数拟合S
Figure 4. The $ \text{p}{{{K}}}_{{\mathrm{a}}} $ calculation based on C-CpHMD: (a) Trajectories of titration coordinate λ and deprotonation fraction S; (b) fitting S to Hill function.
图 5 相对去质子化自由能计算的热力学循环
Figure 5. Thermodynamic cycle of relative deprotonation free energy calculation.
图 6 $ \text{p}{K}_{{\mathrm{a}}} $预测模型性能对比
Figure 6. Comparison of existing $ \text{p}{K}_{{\mathrm{a}}} $ predictors.
-
[1] Casey J R, Grinstein S, Orlowski J 2010 Nat. Rev. Mol. Cell Biol. 11 50
Google Scholar
[2] Qian H, Wu X L, Du X M, Yao X, Zhao X, Lee J, Yang H Y, Yan N 2020 Cell 182 98
Google Scholar
[3] Yang G H, Zhou R, Zhou Q, Guo X F, Yan C Y, Ke M, Lei J L, Shi Y G 2019 Nature 565 192
Google Scholar
[4] Chung H S, Piana-Agostinetti S, Shaw D E, Eaton W A 2015 Science 349 1504
Google Scholar
[5] Nasica-Labouze J, Nguyen P H, Sterpone F, Berthoumieu O, Buchete N, Cote S, Simone A D, Doig A J, Faller P, Garcia A, Laio A, Li M S, Melchionna S, Mousseau N, Mu Y, Paravastu A, Pasquali S, Rosenman D J, Strodel B, Tarus B, Viles J H, Zhang T, Wang C, Derreumaux P 2015 Chem. Rev. 115 3518
Google Scholar
[6] Morrow B H, Payne G F, Shen J 2015 J. Am. Chem. Soc. 137 13024
Google Scholar
[7] Kumar A, Hossain R A, Yost S A, Bu W, Wang Y, Dearborn A D, Grakoui A, Cohen J I, Marcotrigiano J 2021 Nature 598 521
Google Scholar
[8] Singharoy A, Maffeo C, Delgado-Magnero K H, Swainsbury D J K, Sener M, Kleinekathofer U, Vant J W, Nguyen J, Hitchcock A, Isralewitz B, Teo I, Chandler D E, Stone J E, Phillips J C, Pogorelov T V, Mallus M I, Chipot C, Luthey-Schulten Z, Tieleman D P, Hunter C N, Schulten K 2019 Cell 179 1098
Google Scholar
[9] Shimizu H, Tosaki A, Kaneko K, Hisano T, Sakurai T, Nukina N 2008 Mol. Cell Biol. 28 3663
Google Scholar
[10] Ellis C R, Shen J 2015 J. Am. Chem. Soc. 137 9543
Google Scholar
[11] Thurlkill R L, Grimsley G R, Scholtz J M, Pace C N 2006 Protein Sci. 15 1214
Google Scholar
[12] Jensen J H, Li H, Robertson A D, Molina P A 2005 J. Phys. Chem. A 109 6634
Google Scholar
[13] Baptista A M, Martel P J, Petersen S B 1997 Proteins 27 523
Google Scholar
[14] Shi C, Wallace J A, Shen J K 2012 Biophys. J. 102 1590
Google Scholar
[15] Qing R, Hao S L, Smorodina E, Jin D, Zalevsky A, Zhang S G 2022 Chem. Rev. 122 14085
Google Scholar
[16] Henderson J A, Liu R, Harris J A, Huang Y D, de Oliveria V M, Shen J D 2022 Liv. J. Comput. Mol. 4 1563
Google Scholar
[17] Georgescu R E, Alexov E G, Gunner M R 2002 Biophys. J. 83 1731
Google Scholar
[18] Anandakrishnan R, Aguilar B, Onufriev A V 2012 Nucleic Acids Res. 40 W537
Google Scholar
[19] Dolinsky T J, Nielsen J E, McCammon J A, Baker N A 2004 Nucleic Acids Res. 32 665
Google Scholar
[20] Wang L, Li L, Alexov E 2015 Proteins. 83 2186
Google Scholar
[21] Reis Pedro B P S, Vila-Viçosa D, Rocchia W, Machuqueiro M 2020 J. Chem. Inf. Model. 60 4442
Google Scholar
[22] Huang Y D, Yue Z, Tsai C C, Henderson J A, Shen J 2018 J. Phys. Chem. Lett. 9 1179
Google Scholar
[23] Li H, Robertson A D, Jensen J H 2005 Proteins 61 704
Google Scholar
[24] Olsson Mats H M, Søndergaard C R, Rostkowski M, Jensen J H 2011 J. Chem. Theory Comput. 7 525
Google Scholar
[25] Cai Z T, Luo F F, Wang Y X, Li E L, Huang Y D 2021 ACS Omega 6 34823
Google Scholar
[26] Gokcan H, Lsayev O 2022 Chem. Sci. 13 2462
Google Scholar
[27] Chen A Y, Lee J, Damjanovic Ana, Brooks B R 2022 J. Chem. Theory Comput. 184 2673
Google Scholar
[28] Reis Pedro B P S, Bertolini M, Montanari F, Rocchia W, Machuqueiro M, Clevert D A 2022 J. Chem. Theory Comput. 18 5068
Google Scholar
[29] Cai Z T, Liu T Z, Lin Q L, He J H, Lei X W, Luo F F, Huang Y D 2023 J. Chem. Inf. Model 63 2936
Google Scholar
[30] Baptista A M, Teixeira V H, Soares C M 2002 J. Chem. Phys. 117 4184
Google Scholar
[31] Lee M S, Salsbury F R, Brooks Ⅲ C L 2004 Proteins 56 738
Google Scholar
[32] Mongan J, Case D A, McCammon J A 2004 J. Comput. Chem. 25 2038
Google Scholar
[33] Meng Y, Roitberg A E 2010 J. Chem. Theory Comput. 6 1401
Google Scholar
[34] Swails J M, York D M, Roitberg A E 2014 J. Chem. Theory Comput. 10 1341
Google Scholar
[35] Machuqueiro M, Baptista A M 2006 J. Phys. Chem. B 110 2927
Google Scholar
[36] Sequeira J G N, Rodrigues F E P, Silva T G D, Reis Pedro B P S, Machuqueiro M 2022 J. Phys. Chem. B. 126 7870
Google Scholar
[37] Huang Y D, Chen W, Dotson D L, Beckstein O, Shen J 2016 Nat. Commun. 7 12940
Google Scholar
[38] Stern H A 2007 J. Chem. Phys. 126 164112
Google Scholar
[39] Essmann U, Perera L, Berkowitz M L, Darden T, Lee H, Pedersen L G 1995 J. Chem. Phys. 103 8577
Google Scholar
[40] Chen Y, Roux B 2015 J. Chem. Theory Comput. 11 3919
Google Scholar
[41] Radak B K, Chipot C, Suh D, Jo S, Jiang W, Philips J C, Schulten K, Roux B 2017 J. Chem. Theory Comput. 13 5933
Google Scholar
[42] Wang R X, Fang X L, Lu Y P, Yang C Y, Wang S M 2005 J. Med. Chem. 48 4111
Google Scholar
[43] Pieri E, Ledentu V, Sahlin M, Dehez F, Olivucci M, Ferre N 2019 J. Chem. Theory Comput. 15 4535
Google Scholar
[44] de Oliveria V M, Liu R, Shen J 2022 Curr. Opin. Struct. Biol. 77 102498
Google Scholar
[45] Kong X, Brooks III C L 1996 J. Chem. Phys. 105 2414
Google Scholar
[46] Khandogin J, Brooks Ⅲ C L 2005 Biophys. J. 89 141
Google Scholar
[47] Nguyen H, Maier J, Huang H, Perrone V, Simmerling C 2014 J. Am. Chem. Soc. 136 13959
Google Scholar
[48] Huang Y D, Harris R C, Shen J 2018 J. Chem. Inf. Model. 58 1372
Google Scholar
[49] Liu R, Yue Z, Tsai C C, Shen J 2019 J. Am. Chem. Soc. 141 6553
Google Scholar
[50] Harris R C, Liu R, Shen, J 2020 J. Chem. Theory Comput. 16 3689
Google Scholar
[51] Liu R, Zhan S, Che Y, Shen J 2022 J. Med. Chem. 65 1525
Google Scholar
[52] Yao X, Chen C, Wang Y, Dong S, Liu Y, Li Y, Cui Z, Gong W, Perrett S, Yao L, Lamed R, Bayer E A, Cui Q, Feng Y 2020 Sci. Adv. 6 eabd7182
Google Scholar
[53] Verma N, Henderson J A, Shen J 2020 J. Am. Chem Soc. 142 21883
Google Scholar
[54] Arthur E J, Brooks III C L 2016 J. Comput. Chem. 37 2171
Google Scholar
[55] Harris R C, Shen J 2019 J. Chem. Inf. Model. 59 4821
Google Scholar
[56] Wallace J A, Shen J K 2011 J. Chem. Theory Comput. 7 2617
Google Scholar
[57] Henderson J A, Huang Y D, Beckstein O, Shen J 2020 Proc. Natl. Acad. Sci. U. S. A. 117 25517
Google Scholar
[58] Chen W, Huang Y D, Shen J 2016 J. Phys. Chem. Lett. 7 3961
Google Scholar
[59] Yue Z, Li C, Voth G A, Swanson J M J 2019 J. Am. Chem. Soc. 141 13421
Google Scholar
[60] Vo Q N, Mahinthichaichan P, Shen J, Ellis C R 2021 Nat. Commun. 12 984
Google Scholar
[61] Li Z, Zhang X, Wang Q, Li C, Zhang N, Zhang X, Xu B, Ma B, Schrader T E, Coates L, Kovalevsky A, Huang Y D, Wan Q 2018 ACS Catal. 8 8058
Google Scholar
[62] Tsai C C, Yue Z, Shen J 2019 J. Am. Chem. Soc. 141 15092
Google Scholar
[63] Goh G B, Knight J L, Brooks III C L 2012 J. Chem. Theory Comput. 8 36
Google Scholar
[64] Wallace J A, Shen J K 2012 J. Chem. Phys. 137 184105
Google Scholar
[65] Chen W, Shen J K 2014 J. Comput. Chem. 35 1986
Google Scholar
[66] Huang Y D, Chen W, Wallace J A, Shen J 2016 J. Chem. Theory Comput. 12 5411
Google Scholar
[67] Harris J A, Liu R, de Oliveira V M, Vázquez-Montelongo E A, Henderson J A, Shen J 2022 J. Chem. Theory Comput. 18 7510
Google Scholar
[68] Chen W, Wallace J A, Yue Z, Shen J K 2013 Biophys. J. 105 L15
Google Scholar
[69] Wallace J A, Shen J K 2009 Methods Enzymol. 466 455
Google Scholar
[70] Ullmann G M 2003 J. Phys. Chem. B 107 1263
Google Scholar
[71] Goh G B, Hulbert B S, Zhou H, Brooks Ⅲ C L 2014 Proteins 82 1319
Google Scholar
[72] Webb H, Tynan-Connolly B M, Lee G M, Farrell D, O’Meara F, Sondergaard C R, Teilum K, Hewage C, Mclntosh L P, Nielsen J E 2010 Proteins 79 685-702
Google Scholar
[73] Rocklin G J, Mobley D L, Dill K A, Hunenberger P H 2013 J. Chem. Phys. 139 184103
Google Scholar
[74] Bignucolo O, Chipot C, Kellenberger S, Roux B 2022 J. Phys. Chem. B. 126 6868
Google Scholar
[75] Donnini S, Tegeler F, Groenhof G, Grubmüller H 2011 J. Chem. Theory Comput. 7 1962
Google Scholar
[76] Aho N, Buslaev P, Jansen A, Bauer P, Groenhof G, Hess B 2022 J. Chem. Theory Comput. 18 6148
Google Scholar
[77] Buslaev P, Aho N, Jansen A, Bauer P, Hess B, Groenhof G 2022 J. Chem. Theory Comput. 18 6134
Google Scholar
[78] Knight J L, Brooks Ⅲ C L 2011 J. Comput. Chem. 32 3423
Google Scholar
[79] Donnini S, Ullmann R T, Groenhof G, Grubmüller H 2016 J. Chem. Theory Comput. 12 1040
Google Scholar
[80] Huang Y D, Shuai J 2013 J. Phys. Chem. B 117 6138
Google Scholar
[81] Lemkul J A, Huang J, Roux B, MacKerell A D 2016 Chem. Rev. 116 4983
Google Scholar
[82] Khandogin J, Brooks Ⅲ C L 2006 Biochemistry 45 9363
Google Scholar
[83] Itoh S G, Damjanović A, Brooks B R 2011 Proteins 79 3420
Google Scholar
[84] Dashti D S, Meng Y, Roitberg A E 2012 J. Phys. Chem. B. 116 8805
Google Scholar
[85] Swails J M, Roitberg A E 2012 J. Chem. Theory Comput. 8 4393
Google Scholar
[86] Lee J, Miller B T, Damjanovic A, Brooks B R 2015 J. Chem. Theory Comput. 11 2560
Google Scholar
[87] Lee J, Miller B T, Damjanovic A, Brooks B R 2014 J. Chem. Theory Comput. 10 2738
Google Scholar
[88] Henderson J A, Verma N, Harris R, Shen J 2020 J. Chem. Phys. 153 115101
Google Scholar
[89] Kmiecik S, Gront D, Kolinski M, Wieteska L, Dawid A E, Kolinski A 2016 Chem. Rev. 116 7898
Google Scholar
[90] Bennett W D, Chen A W, Donnini S, Groenhof G, Tieleman D P 2013 Can. J. Chem. 91 839
Google Scholar
[91] da Silva F L B, Sterpone F, Derreumaux P 2019 J. Chem. Theory Comput. 15 3875
Google Scholar
[92] Crünewald F, Souza P C T, Abdizadeh H, Barnoud J, de Vries A H, Marrink S J 2020 J. Chem. Phys. 153 024118
Google Scholar
[93] Reilley D J, Wang J, Dokholyan N V, Alexandrova A N 2021 J. Chem. Theory Comput. 17 4583
Google Scholar
[94] Song Y, Mao J, Gunner M R 2009 J. Comput. Chem. 30 2231
Google Scholar
[95] Wang L, Zhang M, Alexov E 2016 Bioinformatics 32 614
Google Scholar
[96] Pahari S, Sun L, Basu S, Alexov E 2018 Proteins 86 1277
Google Scholar
[97] Bas D C, Rogers D M, Jensen J H 2008 Proteins 73 765
Google Scholar
[98] Sun Z, Wang X, Song J 2017 J. Chem Inf. Model. 57 1621
Google Scholar
[99] Stepniewska-Dziubinska M M, Zielenkiewicz P, Siedlecki P 2018 Bioinformatics 34 3666
Google Scholar
[100] Pahari S, Sun L, Alexov E 2019 Database 2019 baz024
Google Scholar
[101] Ancona N, Bastola A, Alexov E 2023 J. Comput. Biophys. Chem. 22 515
Google Scholar
[102] Reis Pedro B P S, Clevert D A, Machuqueiro M 2022 Bioinformatics 38 297
[103] Wei W, Hogues H, Sulea T 2023 J. Chem. Inf. Model. 63 5169
Google Scholar
[104] Coskun D, Chen W, Clark A J, Lu C, Hardr E D, Wang L, Friesner R A, Miller E B 2022 J. Chem. Theory Comput. 18 7193
Google Scholar
[105] Hagg A, Kirschner K N 2023 J. Chem. Inf. Model. 63 4505
Google Scholar
[106] Bueschbell B, Caniceiro A B, Suzano P M S, Machuqueiro M, Rosário-Ferreira N, Moreira I S 2022 Drug Resist. Updat. 60 100811
Google Scholar
DownLoad:
Catalog
Metrics
- Abstract views: 3683
- PDF Downloads: 141
- Cited By: 0
