TY - JOUR

T1 - Probabilistic model to treat flexibility in molecular contacts

AU - Hakulinen, Riku

AU - Puranen, S

PY - 2016

Y1 - 2016

N2 - Evaluating accessible conformational space is computationally expensive and thermal motions are partly neglected in computer models of molecular interactions. This produces error into the estimates of binding strength. We introduce a method for modelling interactions so that structural flexibility is inherently taken into account. It has a statistical model for three-dimensional (3D) properties of non-local contacts and a physics-based description of local interactions, based on mechanical torque. The form of the torque barrier is derived using a representation of the local electronic structure, which is presumed to improve transferability, compared to traditional force fields. The non-local contacts are more distant than 1-4 interactions and target atoms are represented by 3D probability densities. Probability mass quantifies the strength of contact and is calculated as an overlap integral. Repulsion is described by negative probability density, allowing probability mass to be used as the descriptor of contact preference. As a result, we are able to transform the high-dimensional problem into a simpler evaluation of 3D integrals. We outline how this scoring function gives a tool to study the enthalpy-entropy compensation and demonstrate the feasibility of our approach by evaluating numerical probability masses for chosen side chain to main chain contacts in a lysine dipeptide structure.

AB - Evaluating accessible conformational space is computationally expensive and thermal motions are partly neglected in computer models of molecular interactions. This produces error into the estimates of binding strength. We introduce a method for modelling interactions so that structural flexibility is inherently taken into account. It has a statistical model for three-dimensional (3D) properties of non-local contacts and a physics-based description of local interactions, based on mechanical torque. The form of the torque barrier is derived using a representation of the local electronic structure, which is presumed to improve transferability, compared to traditional force fields. The non-local contacts are more distant than 1-4 interactions and target atoms are represented by 3D probability densities. Probability mass quantifies the strength of contact and is calculated as an overlap integral. Repulsion is described by negative probability density, allowing probability mass to be used as the descriptor of contact preference. As a result, we are able to transform the high-dimensional problem into a simpler evaluation of 3D integrals. We outline how this scoring function gives a tool to study the enthalpy-entropy compensation and demonstrate the feasibility of our approach by evaluating numerical probability masses for chosen side chain to main chain contacts in a lysine dipeptide structure.

KW - enthalpy-entropy compensation

KW - internal torque strain

KW - Molecular interactions

KW - negative probability

KW - probabilistic modelling

KW - enthalpy-entropy compensation

KW - internal torque strain

KW - Molecular interactions

KW - negative probability

KW - probabilistic modelling

KW - enthalpy-entropy compensation

KW - internal torque strain

KW - Molecular interactions

KW - negative probability

KW - probabilistic modelling

U2 - 10.1080/00268976.2016.1225129

DO - 10.1080/00268976.2016.1225129

M3 - Artikel

VL - 114

SP - 3201

EP - 3220

JO - Molecular Physics

JF - Molecular Physics

SN - 0026-8976

IS - 21

ER -