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Calculating the free energy of association of transmembrane helices.

ABSTRACT: A large number of experimental studies have been devoted to quantifying the interaction between transmembrane (TM) helices in detergent micelles and, more recently, in bilayers. Theoretical calculation of association free energy of TM helices would be useful for predicting the propensity of given sequences to oligomerize and for understanding the difference between association in micelles and in bilayers. In this article, the theoretical foundation for calculating the standard association free energy of TM helices is laid out and is applied to glycophorin A in both micelles and bilayers. The standard association free energy is decomposed into the effective energy, translational, rotational, and conformational entropy terms. The effective energy of association is obtained by molecular dynamics simulations in an implicit membrane model. The translational and rotational entropy of association is calculated from the probability distribution of the translational and rotational degrees of freedom obtained from the molecular dynamics simulations. The side-chain conformational entropy of association is estimated from the probability distribution obtained by rigid rotation of all side-chain dihedral angles. The calculated standard association free energy of glycophorin A in N-dodecylphosphocholine micelles is in good agreement with the experimental value. The translational entropy cost is larger, whereas the rotational entropy cost is smaller in bilayers than in micelles. The standard association free energy in 1,2-dimyristoyl-sn-glycero-3-phosphocholine bilayers is calculated to be approximately 1.3 kcal/mol more favorable than in N-dodecylphosphocholine micelles, consistent with available experimental data.

SUBMITTER: Zhang J

PROVIDER: S-EPMC1544303 | biostudies-literature | 2006 Sep

REPOSITORIES: biostudies-literature

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Calculating the free energy of association of transmembrane helices.

Zhang Jinming J Lazaridis Themis T

Biophysical journal 20060609 5

A large number of experimental studies have been devoted to quantifying the interaction between transmembrane (TM) helices in detergent micelles and, more recently, in bilayers. Theoretical calculation of association free energy of TM helices would be useful for predicting the propensity of given sequences to oligomerize and for understanding the difference between association in micelles and in bilayers. In this article, the theoretical foundation for calculating the standard association free e ...[more]

PMID: 16766613

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Project description:The free energy of a process is the fundamental quantity that determines its spontaneity or propensity at a given temperature. In particular, the binding free energy of a drug candidate to its biomolecular target is used as an objective quantity in drug design. Recently, binding kinetics-rates of association (k on) and dissociation (k off)-have also demonstrated utility for their ability to predict efficacy and in some cases have been shown to be more predictive than the binding free energy alone. Some methods exist to calculate binding kinetics from molecular simulations, although these are typically more difficult to calculate than the binding affinity as they depend on details of the transition path ensemble. Assessing these rate constants can be difficult, due to uncertainty in the definition of the bound and unbound states, large error bars and the lack of experimental data. As an additional consistency check, rate constants from simulation can be used to calculate free energies (using the log of their ratio) which can then be compared to free energies obtained experimentally or using alchemical free energy perturbation. However, in this calculation it is not straightforward to account for common, practical details such as the finite simulation volume or the particular definition of the "bound" and "unbound" states. Here we derive a set of correction terms that can be applied to calculations of binding free energies using full reactive trajectories. We apply these correction terms to revisit the calculation of binding free energies from rate constants for a host-guest system that was part of a blind prediction challenge, where significant deviations were observed between free energies calculated with rate ratios and those calculated from alchemical perturbation. The correction terms combine to significantly decrease the error with respect to computational benchmarks, from 3.4 to 0.76 kcal/mol. Although these terms were derived with weighted ensemble simulations in mind, some of the correction terms are generally applicable to free energies calculated using physical pathways via methods such as Markov state modeling, metadynamics, milestoning, or umbrella sampling.

Dataset Information

Calculating the free energy of association of transmembrane helices.

Publications

Calculating the free energy of association of transmembrane helices.

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