## Overview

The current implementation of RosettaMP uses the same science (i.e. score terms) of the original RosettaMembrane implementation. To increase the flexibility & user-friendliness, we implemented a new interface for these terms. The science & interface for the low- and high-resolution scoring functions are described below.

## Low Resolution Scoring Function

The Rosetta low resolution (centroid-based) energy function for membrane proteins was developed in 2006 with the Membrane Ab Initio folding protocol (Yarov-Yaravoy et al. 2006). It was derived from 28 alpha helical membrane proteins and is knowledge-based.

### Membrane Representation

The low resolution energy function divides the membrane bilayer into two or five layers describing various regions of the membrane environment. Scoring per-residue, residue-residue and packing interactions depends upon position in a specific layer. The five-layer representation is described below:

### Scoring Function

The energy function includes six terms: a residue-environment energy, residue-residue energy, packing density, termini penalty, non-helix penalty, and TMprojection penalty.

For a detailed description of all score terms, their functional form and their weights for specific applications, please see Alford, Koehler Leman et al.

### Individual energy terms

Terms, corresponding energy methods, and usage are described below. The score name is the name of the term you would use when setting up a weights file.

#### Membrane Residue-Environment Term

Score Name: MPEnv. Score per-residue interactions with the membrane environment using a 5 layer membrane (Layers: inner hydrophobic, outer hydrophobic, interface, polar, water). Energy Method type: One body context-dependent. For Developers - code in core/scoring/membrane/MPEnvEnergy.hh.

#### Membrane Residue-Residue Pair Term

Score Name: MPPair. Score residue-residue interactions in the membrane environment using a 2 layer membrane (Layers: hydrophobic, polar). Energy Method Type: Two-body context dependent. For Developers - code in core/scoring/membrane/MPPairEnergy.hh

#### Membrane Packing Density Term

Score Name: MPCBeta. Score packing-density in the membrane based on the number of helices. Energy Method Type: One Body context dependent. For Developers - code in core/scoring/membrane/MPCbetaEnergy.hh

#### Membrane Termini Penalty

Score Name: MPTermini. Penalty for termini residues (N- or C- termini) in the membrane. Energy Method Type: Whole structure energy. For Developers - code in /core/scoring/membrane/MPTerminiPenalty.hh

#### Membrane TM Projection Penalty

Score Name: MPTMProj. Penalty for helices longer than thickness of the membrane. Energy Method type: Whole Structure Energy. For Developers - code in core/scoring/membrane/MPTMProjPenalty.hh

#### Membrane Non Helix Penalty

Score Name: MPNonHelix. Penalty for non helix residues in the membrane. Uses Secondary structure in Rosetta (or provided). Energy Method Type: One body context independent energy. For Developers - code in core/scoring/membrane/MPNonHelixPenalty.hh

### Score Options

Option Name Description Type
score:find_neighbors_3dgrid Use 3D lookup table in neighbor calculations boolean
membrane:no_interpolate_Mpair switch off interpolation between 2 layers when a pair of residues is on the boundary boolean

## High-Resolution Scoring Function

The Rosetta high resolution (all atom) energy function was developed in 2007 with the high-resolution ab initio and refinement protocols (Barth et al. 2007) and is based on the Implicit Membrane Model by Lazaridis (2003).

### Membrane Representation

The high-resolution energy function represents the membrane bilyaer as a hydrophobic slab of fixed thickness, T (where the default thickness is 30Ang). This gives a hydrophobic core of 18A with transition regions of 6A on either side. This membrane representation is illustrated below:

### Scoring function

The high-resolution score function combines terms from the score12 energy function with terms for membrane solvation, environment and a correction for strength of hydrogen bonds in the membrane.

For a detailed description of all score terms, their functional form and their weights for specific applications, please see Alford, Koehler Leman et al.

### Individual Energy Terms

#### Membrane Solvation

Score Name: fa_mpsolv. Score a pair of residues given their depth in the membrane bilayer

#### Membrane environment

Score Name: fa_mpenv. Score a single residue given its depth in the membrane bilayer

### Score Options

Option Name Description Type
mp:scoring:hbond Hydrogen bonding energy correction for membrane proteins. Default = false. boolean

## References

• Alford RF, Koehler Leman J, Weitzner BD, Duran A, Tiley DC, Gray JJ (2015). An integrated framework advancing membrane protein modeling and design. PLoS Comput. Biol. - In Press - Rosetta Revision #57518
• Yarov-Yarovoy V, Schonbrun J, Baker D. (2006 Mar 1) Multipass membrane protein structure prediction using Rosetta. Proteins. 62(4):1010-25.
• Barth P, Schonbrun J, Baker D. (2007 Oct 2) Toward high-resolution prediction and design of transmembrane helical protein structures. Proc Natl Acad Sci U S A. 104(40):15682-7.
• Barth P, Wallner B, Baker D. (2009 Feb 3) Prediction of membrane protein structures with complex topologies using limited constraints. Proc Natl Acad Sci U S A. 106(5):1409-14.