OPEP6: A New Constant-pH Molecular Dynamics Simulation Scheme with OPEP Coarse-Grained Force Field

Author(s)

Barroso da Silva, Fernando Luis ^{[1, 2, 3, 4]} ; Sterpone, Fabio ^{[1, 4]} ; Derreumaux, Philippe ^{[5, 6]}

Affiliation

^[1] Univ Sorbonne Paris Cite, 13 Rue Pierre & Marie Curie, F-75005 Paris - France

^[2] North Carolina State Univ, Dept Chem & Biomol Engn, Raleigh, NC 27606 - USA

^[3] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Fis & Quim, Ave Cafe S-No, BR-14040903 Sao Paulo - Brazil

^[4] Univ Paris Diderot Paris 7, Inst Biol Physico Chim, Lab Biochim Theor, UPR 9080, CNRS, 13 Rue Pierre & Marie Curie, F-75005 Paris - France

^[5] Ton Duc Thang Univ, Lab Theoret Chem, Ho Chi Minh City - Vietnam

^[6] Ton Duc Thang Univ, Fac Pharm, Ho Chi Minh City - Vietnam

• Document type: Journal article
• Source: JOURNAL OF CHEMICAL THEORY AND COMPUTATION; v. 15, n. 6, p. 3875-3888, JUN 2019.
• Web of Science Citations: 2

Abstract

The great importance of pH for molecular processes has motivated the continuous development of numerical methods to improve the physical description of molecular mechanisms in computer simulations. Although rigid titration models are able to provide several pieces of useful information, the coupling between the molecular conformational changes and the acid base equilibrium is necessary to more completely model the pH effects in biomolecules. Previously reported convergence issues with atomistic simulations indicated that a promising approach would require coarse-grained models. By means of the coupling between the successful OPEP force field for proteins with the fast proton titration scheme, we proposed a new protocol for constant-pH molecular dynamics simulations that takes advantage of both coarse-grained approaches to circumvent sampling difficulties faced by other numerical schemes and also to be able to properly describe electrostatic and structural properties at lower CPU costs. Here, we introduce this new protocol that defines now OPEP6 and its pK(a)'s benchmark for a set of representative proteins (HP36, BBL, HEWL, NTL9, and a protein G variant). In comparison with experimental measurements, our calculated pK(a) values have the average, maximum absolute, and root-mean square deviations of {[}0.3-1.1], {[}0.6-2.5], and {[}0.4-1.3] pH units, respectively, for these five studied proteins. These numbers are within the ones commonly observed when similar comparisons are done among different theoretical models and are slightly better than the accuracy obtained by a rigid model using the same titration engine. For BBL, the predicted pK(a) are closer to experimental results than other analyzed theoretical data. Structural properties were tested for insulin where separation distances between the groups were compared and found in agreement with experimental crystallographic data obtained at different pH conditions. These indicate the ability of the new OPEP to properly describe the system physics and open up more possibilities to study pH-mediated biological processes. (AU)

• FAPESP's process: 15/16116-3 - Molecular mechanisms of electrostatic origin responsible for protein complexation
• Grantee: Fernando Luis Barroso da Silva
• Support Opportunities: Regular Research Grants