Specific and Non-Specific Protein Association in Solution: Computation of Solvent Effects and Prediction of First-Encounter Modes for Efficient Configurational Bias Monte Carlo Simulations

Abstract

Weak and ultra-weak protein-protein association play a role in molecular recognition, and can drive spontaneous self-assembly and aggregation. Such interactions are difficult to detect experimentally, and are a challenge to the force field and sampling technique. A method is proposed to identify low-population protein-protein binding modes in aqueous solution. The method is designed to identify preferential first-encounter complexes from which the final complex(es) at equilibrium evolves. A continuum model is used to represent the effects of the solvent, which accounts for short- and long-range effects of water exclusion and for liquid-structure forces at protein/liquid interfaces. These effects control the behavior of proteins in close proximity and are optimized based on binding enthalpy data and simulations. An algorithm is described to construct a biasing function for self-adaptive configurational-bias Monte Carlo of a set of interacting proteins. The function allows mixing large and local changes in the spatial distribution of proteins, thereby enhancing sampling of relevant microstates. The method is applied to three binary systems. Generalization to multiprotein complexes is discussed.

Impact of subdomain D1 of the short form S1b of the human prolactin receptor on its inhibitory action on the function of the long form of the receptor induced by prolactin

“…To estimate the strength of the electrostatic interactions between monomers in the WT and mutant dimers dissociation energies were calculated [15] by gradual heating, using rigid-body Monte Carlo simulation [16] (Fig. 5D).…”

Computational study of the inhibitory mechanism of the kinase CDK5 hyperactivity by peptide p5 and derivation of a pharmacophore

“…The study builds upon a series of recent developments on ab initio complex structure prediction [21, 22] and force field optimization [23–25]. The predicted binding modes suggest that p5 is a non-selective competitive inhibitor of p25, in accordance with available experimental data.…”

“…The prediction of the CDK5-p5 complex structure in aqueous solution and at physiological conditions follows the general method described in [21, 22]. The method consists of three stages, in this case: i) prediction of p5 and CDK5 conformers in solution; ii) identification of CDK5-p5 pre-relaxation binding modes; and iii) structural relaxation of the complexes at physiological conditions.…”

“…The method used to predict the binding modes consists of two consecutive stages [21, 22]: a prescreening of favorable CDK5-p5 interactions aimed to identify physically relevant first-encounter modes, followed by a configurational biased sampling to identify statistically relevant conformational families of the complex. Both stages were described in detail previously [21, 22]; briefly, the prescreening consists of a simulated-annealing MC optimization of an electrostatic norm e and a hydrophobic norm h [21].…”

Role of Albumin in the Formation and Stabilization of Nanoparticle Aggregates in Serum Studied by Continuous Photon Correlation Spectroscopy and Multiscale Computer Simulations

“…The interaction energy between two proteins is divided into electrostatic and van der Waals contributions, in the form $V_{P-P^{\prime }}=V_{P-P^{\prime }}^{\mathit{elec}}+V_{P-P}^{\mathit{elec}}+V_{P^{\prime }-P^{\prime }}^{\mathit{elec}}+V_{P-P^{\prime }}^{\nu dW}$. The electrostatic terms are represented by the screened Coulomb potentials implicit solvent model (SCPISM), 31,32 as…”