Development of Continuous Constant pH Molecular Dynamics (CpHMD)

In recent years, Shen lab further developed CpHMD to improve the accuracy and generalizability. The developments includes the GB-Neck2 based CpHMD, the hybrid-solvent and all-atom GRF and PME CpHMD. Our goal is to offer an accurate, reliable and computational efficient pH-controlling tool (pH stat) to the community in the near future. The CpHMD tools are implemented in both CHARMM and Amber packages.

GPU implementations are under way.

Harris RC and Shen J*, 

GPU-accelerated implementation of continuous constant pH molecular dynamics in Amber: pKa predictions with single pH simulations

J Chem Inf Model 59: 4821-4832, 2019.

D.A. Case, I.Y. Ben-Shalom, S.R. Brozell, D.S. Cerutti, T.E. Cheatham, III, V.W.D. Cruzeiro, T.A. Darden, R.E. Duke, D. Ghoreishi, M.K. Gilson, H. Gohlke, A.W. Goetz, D. Greene, R Harris, N. Homeyer, S. Izadi, A. Kovalenko, T. Kurtzman, T.S. Lee, S. LeGrand, P. Li, C. Lin, J. Liu, T. Luchko, R. Luo, D.J. Mermelstein, K.M. Merz, Y. Miao, G. Monard, C. Nguyen, H. Nguyen, I. Omelyan, A. Onufriev, F. Pan, R. Qi, D.R. Roe, A. Roitberg, C. Sagui, S. Schott-Verdugo, J. Shen, C.L. Simmerling, J. Smith, R. Salomon-Ferrer, J. Swails, R.C. Walker, J. Wang, H. Wei, R.M. Wolf, X. Wu, L. Xiao, D.M. York and P.A. Kollman (2018),

AMBER 2018, University of California, San Francisco.

Huang YD, Harris RC, Shen J*, 

Generalized Born based continuous constant pH molecular dynamics in Amber: implementation, benchmarking,

and analysis. 

J Chem Inf Model 58:1372-1383, 2018.

Huang YD, Chen W, and Shen J*,

Continuous constant pH molecular dynamics with particle-mesh Ewald and titratabe water.

J Chem Theory Comput. 12: 5411-5421, 2016.

Chen W and Shen J*,

Effects of system net charge and electrostatic truncation on all-atom constant pH molecular dynamics.

J Comput Chem 35: 1986-1996, 2014.

Chen W, Wallace JA, Yue Z, and Shen JK*,
Introducing titratable water to all-atom molecular dynamics at constant pH.
Biophys J 105: L15-L17, 2013.

Wallace JA and Shen JK*,
Charge-leveling and proper treatment of long-range electrostatics in all-atom molecular dynamics at constant pH.
J Chem Phys 137: 184105, 2012.

Wallace JA and Shen JK*,

Continuous constant pH molecular dynamics in explicit solvent with pH-based replica exchange.

J Chem Theory Comput 7: 2617-2629, 2011.

The first-generation CpHMD technique was developed in the Brooks group. This method utilizes the generalized Born implicit-solvent model for both conformational and protonation state sampling. It was recognized as one of the most accurate pKa prediction tools in the blind protein pKa prediction exercise in 2009. 

Khandogin J* and Brooks CL III,

Constant pH molecular dynamics simulation with proton tautomerism.

Biophys J 89: 141-157, 2005.

Khandogin J and Brooks CL III*,

Toward the accurate first-principles prediction of ionization equilibria in proteins. 

Biochemistry 45: 9363-9373, 2006.