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Adaptative Steered Molecular Dynamics Study of Mutagenesis Effects on Calcium Affinity in the Regulatory Domain of Cardiac Troponin C.

ABSTRACT: Calcium-dependent cardiac muscle contraction is regulated by the protein complex troponin (cTn) and specifically by the regulatory N-terminal domain (N-cTnC) which contains one active Ca²⁺ binding site (site II). It has been previously shown that cardiac muscle contractility and functionality is affected by mutations in N-cTnC which alter calcium binding affinity. Here, we describe the application of adaptive steered molecular dynamics to characterize the influence of N-cTnC mutations on site II calcium binding affinity. We observed the correct trends for all of the studied calcium sensitizing and desensitizing mutants, in conjunction with loop II perturbations. Additionally, the potential of mean force accuracy was shown to increase substantially with increasingly slower speeds and using fewer trajectories. This study presents a novel approach to computationally estimate the Ca²⁺ binding affinity of N-cTnC structures and is a valuable potential tool to support the design and characterization of novel mutations with potential therapeutic benefits.

SUBMITTER: Hantz ER

PROVIDER: S-EPMC8350873 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Adaptative Steered Molecular Dynamics Study of Mutagenesis Effects on Calcium Affinity in the Regulatory Domain of Cardiac Troponin C.

Hantz Eric R ER Lindert Steffen S

Journal of chemical information and modeling 20210603 6

Calcium-dependent cardiac muscle contraction is regulated by the protein complex troponin (cTn) and specifically by the regulatory N-terminal domain (N-cTnC) which contains one active Ca<sup>2</sup><sup>+</sup> binding site (site II). It has been previously shown that cardiac muscle contractility and functionality is affected by mutations in N-cTnC which alter calcium binding affinity. Here, we describe the application of adaptive steered molecular dynamics to characterize the influence of N-cTn ...[more]

PMID: 34080877

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Project description:Computing protein-protein association affinities is one of the fundamental challenges in computational biophysics/biochemistry. The overwhelming amount of statistics in the phase space of very high dimensions cannot be sufficiently sampled even with today's high-performance computing power. In this article, we extend a potential of mean force (PMF)-based approach, the hybrid steered molecular dynamics (hSMD) approach we developed for ligand-protein binding, to protein-protein association problems. For a protein complex consisting of two protomers, P1 and P2, we choose m (≥3) segments of P1 whose m centers of mass are to be steered in a chosen direction and n (≥3) segments of P2 whose n centers of mass are to be steered in the opposite direction. The coordinates of these m + n centers constitute a phase space of 3(m + n) dimensions (3(m + n)D). All other degrees of freedom of the proteins, ligands, solvents, and solutes are freely subject to the stochastic dynamics of the all-atom model system. Conducting SMD along a line in this phase space, we obtain the 3(m + n)D PMF difference between two chosen states: one single state in the associated state ensemble and one single state in the dissociated state ensemble. This PMF difference is the first of four contributors to the protein-protein association energy. The second contributor is the 3(m + n - 1)D partial partition in the associated state accounting for the rotations and fluctuations of the (m + n - 1) centers while fixing one of the m + n centers of the P1-P2 complex. The two other contributors are the 3(m - 1)D partial partition of P1 and the 3(n - 1)D partial partition of P2 accounting for the rotations and fluctuations of their m - 1 or n - 1 centers while fixing one of the m/n centers of P1/P2 in the dissociated state. Each of these three partial partitions can be factored exactly into a 6D partial partition in multiplication with a remaining factor accounting for the small fluctuations while fixing three of the centers of P1, P2, or the P1-P2 complex, respectively. These small fluctuations can be well-approximated as Gaussian, and every 6D partition can be reduced in an exact manner to three problems of 1D sampling, counting the rotations and fluctuations around one of the centers as being fixed. We implement this hSMD approach to the Ras-RalGDS complex, choosing three centers on RalGDS and three on Ras (m = n = 3). At a computing cost of about 71.6 wall-clock hours using 400 computing cores in parallel, we obtained the association energy, -9.2 ± 1.9 kcal/mol on the basis of CHARMM 36 parameters, which well agrees with the experimental data, -8.4 ± 0.2 kcal/mol.

Dataset Information

Adaptative Steered Molecular Dynamics Study of Mutagenesis Effects on Calcium Affinity in the Regulatory Domain of Cardiac Troponin C.

Publications

Adaptative Steered Molecular Dynamics Study of Mutagenesis Effects on Calcium Affinity in the Regulatory Domain of Cardiac Troponin C.

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